Multimodal brain sensing lead

ABSTRACT

A medical lead with at least a distal portion thereof implantable in the brain of a patient is described, together with methods and systems for using the lead. The lead is provided with at least two sensing modalities (e.g., two or more sensing modalities for measurements of field potential measurements, neuronal single unit activity, neuronal multi unit activity, optical blood volume, optical blood oxygenation, voltammetry and rheoencephalography). Acquisition of measurements and the lead components and other components for accomplishing a measurement in each modality are also described as are various applications for the multimodal brain sensing lead.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a divisional of U.S. application Ser. No.13/673,312, titled “Multimodal Brain Sensing Lead,” filed Nov. 9, 2012,now U.S. Pat. No. 10,123,717, which claims the benefit of U.S.Provisional Application Ser. No. 61/558,382, filed on Nov. 10, 2011,each of which is expressly incorporated by reference herein in itsentirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of theDepartment of Commerce, National Institutes of Standards and Technology,Cooperative Agreement No. 70NANB7H7001.

FIELD OF THE INVENTION

The present technology relates generally to systems and methods fordetecting neurological dysfunction and other conditions, and moreparticularly, to a system and method for acquiring measurementscorresponding to activity in or near a brain in multiple sensingmodalities.

BACKGROUND

Increasingly, implantable active medical device systems are being usedor investigated for use in treatment protocols or other therapies for avariety of neurological conditions or disorders. For example,implantable active medical device systems are known that rely upon animplanted pulse generator (IPG) or neurostimulator in operablecommunication with one or more electrodes (such as via electrode-bearingleads) to deliver a form of electrical stimulation (e.g.,charge-balanced pulsatile stimulation) to the neural tissue of apatient. The stimulating elements and the form of stimulation may beconfigured based on the specific application of the system.

For example, electrodes may be implanted at or near particularanatomical structures or in particular neural circuits in a patient'sbrain and the stimulation parameters (e.g., amplitude and duration) maybe optimized for addressing the symptoms of a movement disorder such asParkinson's disease (e.g., tremor or bradykinesia). Similarly,electrodes may be located at deep brain structures that are understoodto be related to major depressive disorder (MDD) and the parametersgoverning the stimulation selected to alleviate the condition. Manyother potential applications of neurostimulation are being explored foraddressing a wide variety of conditions or disorders understood to havea neurological connection, ranging from gastrointestinal disorders likegastroesophageal reflux disease (GERD) and obesity to migraineheadaches. Still other applications of implantable active medical devicesystems include encouraging recovery of the brain from stroke.

Active implantable medical device systems have been used in clinicaltrials for patients with epilepsy in which an implanted neurostimulatormay be configured to monitor electrographic signals sensed on one ormore channels using sensing elements (such as macroelectrodes) that areimplanted in or on the patient's brain. The neurostimulator further maybe configured to process the sensed signals and to recognize one or morepatterns occurring in the signals. The neurostimulator may have avariety of tools or algorithms that can be programmed to recognizecertain patterns or sequences or other combinations of patterns whenthey occur in the sensed signals as “events.” A given event may beunderstood to be related in some way to the patient's epilepsy (e.g., anevent may be categorized as a precursor to a seizure or as a “seizureonset” or as a fully developed seizure). Additionally, theneurostimulator may be configured to generate and deliver through one ormore stimulation elements a form of electrical stimulation therapywhenever it detects a particular event or events. Since in this systemthe neurostimulator can be configured to respond to events by deliveringstimulation, the system is referred to as a responsive neurostimulationsystem. Once such responsive neurostimulation system is manufacturedunder the tradename the “RNS SYSTEM” by NeuroPace, Inc.

In many implantable neurostimulator systems, one or more externalcomponents may be configured for selective communication with theimplanted neurostimulator (e.g., using inductive telemetry). A“programmer” is the name commonly used to refer to one of these externalcomponents, and it is used by a patient's physician to initially programor to reprogram the operating parameters of the neurostimulator). Aprogrammer also may be configured to assess a state or condition of theneurostimulator (e.g., whether the neurostimulator is enabled to deliverstimulation or how much remaining life there is on the neurostimulator'sprimary cell or rechargeable battery). If the neurostimulation system isa responsive one and therefore one that acquires anti/or storesinformation sensed from the patient, then the programmer may also beused to interrogate the neurostimulator as to data the neurostimulatoreither has stored or is receiving in real time corresponding to thesensed signals.

A “remote monitor” is the name commonly used to refer to another ofthese external components, and it is used by the patient to communicatewith the neurostimulator and to accomplish some limited set of functions(e.g., to disable stimulation, to cause the neurostimulator to store arecord corresponding to a sensed signal at a time when the patientsubjectively believes an “event” or a seizure might be occurring, and todownload data from the neurostimulator so that it can be directed to acentralized database where the patient's physician can review it andperhaps otherwise manipulate it).

Electrical stimulation thus is an established therapy for treating someneurological disorders and responsive electrical stimulation is anemerging therapy for treating epilepsy and may be useful in treatingother disorders and conditions. In responsive neurostimulation, deliveryof therapy is triggered in response to information acquired about aphysiological condition of a particular location or locations in or onthe patient's brain (e.g., field potential measurements acquired fromelectrodes implanted at or near what is understood to be a focus ofepileptiform activity for the patient). It will be appreciated that thesuccess of a particular electrical stimulation therapy, at least to somedegree, may be related to the quality and quantity of the physiologicalinformation that is relied upon to trigger that therapy. Moreover, thisis likely to be the case regardless of which neurological disorder orcondition the therapy is intended to treat (e.g., epilepsy, migraineheadaches, movement disorders, etc.).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side, partial sectional view of a proximal portion of amultimodal depth brain sensing lead according to an embodiment.

FIG. 2 is a cross-sectional view of a lead contact of FIG. 1.

FIG. 3 is an end view of a lead contact of FIG. 1.

FIG. 4 is an enlarged side view of a proximal end cap that may be usedwith the proximal portion shown in FIG. 1.

FIG. 5A is a side view of a portion of a multimodal sensing lead bodyaccording to an embodiment.

FIG. 5B is cross-sectional view taken along the line A-A of FIG. 5A.

FIG. 6 is a side, partial sectional view of a distal portion of amultimodal deep brain sensing lead according to an embodiment.

FIG. 7 is an enlarged view of an electronics module of FIG. 6.

FIG. 8 is a cross-sectional view of a shaft associated with theelectronics module of FIG. 7.

FIG. 9 is a side, partial sectional view of a macroelectrode which maybe used with a multimodal brain sensing lead according to embodiments.

FIG. 10 is a cross-sectional view of the macroelectrode of FIG. 9,

FIG. 11A is a side, partial sectional view of a microelectrode assemblywhich may be used with a multimodal brain sensing lead according toembodiments.

FIG. 11B is a cross-sectional view taken along the line B-B of themicroelectrode assembly of FIG. 11A.

FIG. 12 is a side, partial sectional view of an optical assemblyincluded in the distal portion of FIG. 6, in accordance with anembodiment.

FIG. 13 is a side, enlarged view of the distal tip of FIG. 6, inaccordance with an embodiment.

FIG. 14 is a bottom, partial sectional view of a distal portion of amultimodal strip sensing lead, in accordance with an embodiment.

FIG. 15 is a side partial sectional view of the distal portion of FIG.14.

FIG. 16 is a series of graphs representing the type of information thatmight be obtained over time from each of five different sensingmodalities and then displayed to a user in accordance with embodiment.

FIG. 17 is a schematic illustration of an example of how data obtainedfrom a multimodal brain sensing lead might be used in a closed-looptherapy delivery system in accordance with embodiments.

FIG. 18 is a graphical illustration of the timing that an oxygenationmeasurement modality of a multimodal brain sensing lead might useaccording to an embodiment.

FIG. 19 is a schematic diagram of an example of an implantable medicaldevice system with which a multimodal brain sensing lead according toembodiments may be used.

FIG. 20 is a block diagram illustrating the functional relationship ofsome of the implantable components of an implantable medical devicesystem, with which embodiments of a multimodal brain sensing lead may beused.

FIG. 21A is a table, referred to herein as Table 2, that illustrates thetiming of measurement acquisition for various sensing modalities overone minute.

FIG. 21B is a table, referred to herein as Table 3, that illustrates thetiming of measurement acquisition for various sensing modalities overone minute.

The drawings referred to in this description should not be understoodstood as being drawn to scale unless specifically noted.

DESCRIPTION OF EMBODIMENTS

Various embodiments are described below, with reference to detailedillustrative embodiments, in the context of an implantable medical leadwith multimodal sensing capability. It will be apparent from thedescription provided herein that the devices, systems, and methods canbe embodied in a wide variety of forms. Consequently, the specificstructural and functional details disclosed herein are representativeand do not limit the scope of embodiments of the present technology.

Overview

A multimodal brain sensing lead is an implantable probe designed tocollect physiological measurements using multiple sensing modalities allfrom a local region in a patient's brain. The timing of eachphysiological measurement may be multiplexed with the otherphysiological measurements, for example, so that all the measurementsare acquired at close to the same time (to approximate concurrentsensing in multiple modes). The sensing modalities may include one ormore of the following: (1) neuronal field potential (FP) measurements;(2) neuronal single unit activity (SUA) measurements; (3) neuronal multiunit activity (MUA) measurements; (4) rheoencephalography (REG)measurements; (5) neurochemical and pharmaceutical voltammetric (VM)measurements; (6) optical blood volume (OBV) measurements; and (7)optical blood oxygenation (OBO) measurements.

Desirably, the sensing modalities are implemented on the lead in a waythat is conducive to having the lead remain in the patient's brainchronically, as opposed to acutely in, for example, a hospital setting.Implementing multiple sensing modalities on a single brain lead foracquiring localized physiological data chronically may be expected toresult in excellent long-term visibility into physiological changeswithin the human brain.

Generally, neuronal field potential measurements describe the activityof large populations of neurons near the sensing electrodes. Thisactivity may be used to detect pathological neurological events such asepileptic seizures and migraine. Neuronal single unit activitymeasurements describe the firing rates and patterns of single neurons.Neuronal multi unit activity measurements describe the firing rates andpatterns of small local populations of neurons. While single unitactivity measurements and multi unit activity measurements may beacquired using the same components on a multimodal brain sensing lead,and in fact this is the case in the embodiments described herein, eachis considered a separate and distinct modality.

Certain single unit activity and multi unit activity firing patterns andrates are understood to be indicative of pathological states such asParkinsonian tremor and subthalamic disinhibition. The relationshipbetween single unit activity, multi unit activity and field potentialmeasurements may be used to determine whether individual neurons orlocal populations of neurons are firing in a coordinated manner relativeto a larger population of neurons.

Voltammetry measurements reflect concentrations of oxidizable andreducible drugs and neurochemicals. Neurochemicals may includeneurotransmitters such as serotonin, dopamine, epinephrine andnorepinephrine. Neurochemicals also may include other signalingmolecules such as nitric oxide and hormones. Additionally, oxygen andhydrogen ions (i.e., pH) are neurochemicals that reflect metabolism andcan be measured using voltammetry.

Drugs that may be measured using voltammetry include L-DOPA (brand nameSinemet), which is used to treat Parkinson's disease, and fluoxetine(brand name Prozac), which is a serotonergic drug used to treat mentaldisorders such as depression, obsessive compulsive disorder (OCD),eating disorders and panic attacks. These measurements can be used tomeasure drug levels directly at a therapeutic target, as a functionalassay of the drug's effect on the release of neurochemicals.Voltammetric measurements also may be used to assay the physiologicalrelease of neurochemicals important in certain diseases such as movementdisorders and depression.

Optical blood volume (OBV) and optical blood oxygenation (OBO)measurement methods can be used to measure hemodynamic variables,including blood volume, blood oxygenation, and heart rate. These methodsuse wavelengths that are specifically absorbed by oxygenated anddeoxygenated hemoglobin. Additionally, blood flow can be estimated fromoptical blood volume measurements, since when blood flow increases, therelative ratio of blood volume to tissue increases. As was the case withthe single unit activity measurement modality and the multi unitactivity measurement modality, the optical blood volume measurementmodality is considered to be a modality that is separate and distinctfrom the optical blood oxygenation measurement modality. This is thecase even though both of the optical blood volume measurement modalityand the optical blood oxygenation measurement modality may beaccomplished using the same components on the multimodal brain sensinglead as, in fact, is the case with embodiments of a multimodal brainsensing lead described herein.

It likely is advantageous to measure hemodynamic variables in the samevicinity as the other physiological variables measurable by themultimodal brain sensing lead at least for the reason that a combinationof diverse physiological measurements is likely to provide a morecomplete description of the physiological state of the tissue than isany one variable alone.

Hemodynamic variables vary between regions of the body and braindepending on local variables such as disease state and metabolicactivity. Blood flow and blood oxygenation are important in diseasessuch as epilepsy, depression and migraine. For example, abnormal bloodflow can be associated with seizures and with migraine aura andheadache, and abnormal blood flow in limbic and cortical regions can beassociated with major depression.

Rheoencephalography is the measurement of tissue impedance usingelectrical waveforms. Rheoencephalography can provide a measure ofcombined neuronal activity and blood flow. Rheoencephalographymeasurements are correlated with blood flow because blood has a lowerelectrical resistance than brain tissue. For example, when blood flowincreases in a brain area, the blood vessels increase in diameter,resulting in an increased blood volume-to-brain tissue ratio. Becauseblood, has a lower electrical resistance than brain tissue, theelectrical impedance through the area with increased blood flow isdecreased.

Rheoencephalography measurements are also correlated with neuronalactivity, because neurons decrease in volume when they become moreactive, causing increased intercellular space and lower electricalimpedance. For example, when neurons in a particular brain area becomeactive, these neurons shrink slightly, thus increasing the ratio ofextracellular fluid to neuronal cell volume. This leads to decreasedelectrical impedance because extracellular fluid has lower impedancethan neuronal cell bodies. Since rheoencephalography combines bloodvolume and electrophysiological metrics, it can be used to corroborateboth hemodynamic and electrophysiological measurements. It is alsopossible that rheoencephalography measurements may be correlated inother clinically useful ways with disease symptoms and pathologies.

The information from multiple sensing modalities provided by embodimentsmay enable a clinician to more accurately characterize disease states,assess responses to therapeutic interventions, and make better informedadjustments to a patient's therapy. When a multimodal brain sensing leadaccording to embodiments is used to acquire different types ofinformation over time, the information can beneficially provide numerousopportunities to adjust therapy based on the type, magnitude, andtemporal patterns of observed physiological signs. For example, abnormalneuronal activity or blood flow changes might change, quite often in anindependent manner, but the coincidence of both signs might signal aclinically relevant event and be used to trigger therapy delivery.Therapy can be fine tuned based on multimodal information, even withoutan understanding of its causal relationship to the patient's state.Specifically, signs that would otherwise be unobservable can bemonitored and/or relationships, the significance of which may not bewell understood, can be used to inform a patient's treatment with lessreliance on patient-reported symptoms and externally observable signs.

Additionally, when embodiments of the multimodal brain sensing lead areused as part of a closed-loop, responsive therapy implantable deliverysystem, and numerous opportunities become available to deliver therapybased on the timing and concordance of observed physiological signs. Forexample, abnormal neuronal activity or blood flow changes might occurindependently quite often, but the coincidence of both signs mightsignal a clinically relevant event and be used to trigger therapydelivery.

The discussion will begin with a summary of various embodiments. Then adescription of embodiment characteristics will follow. The discussioncontinues with a more particularized description of the multimodal lead,including gross dimensions and various components. The discussion thenturns to a description of measurement acquisition, measurementacquisition timing and uses of acquired measurements. Finally, clinicalexamples are discussed.

Characteristics of Embodiments

Embodiments of the multimodal brain sensing lead include chronicallyimplantable miniaturized sensors that are configured for multimodalsensing from a localized brain area with multiplexed timing. Embodimentsof the multimodal brain sensing lead may include one or more of thefollowing features: (1) multimodal sensing using sensors carried by asingle probe or lead to allow highly localized monitoring; (2) sensingusing the various modalities at around the same time or at coordinatedtimes; and (3) MRI safety.

Chronic Implantability

Two major challenges are associated with providing a brain lead that canbe chronically implanted. First, for the lead to be implantable, it mustbe made of materials that are biocompatible and safe to the patient. Allof the materials included in embodiments of the multimodal brain sensinglead described here are generally considered to be safe andbiocompatible. More particularly, the materials may include: silicone; a90% platinum, 10% iridium alloy (a.k.a. Ptlr); polyether ether ketone(a.k.a. PEEK); vitreous carbon (a.k.a. glassy carbon); glass; sapphire;titanium; tantalum; biocompatible epoxy; and ethylenetetrafluoroethylene (a.k.a. ETFE).

Second, for sensors to be implantable, they must be designed andconstructed in such a way that they can function robustly inside thebody, and desirably will continue to function for the life of thepatient, without having to be replaced. Embodiments of the multimodalbrain sensing lead and the sensors used in connection therewith includedesign features that support chronic implantability. One such designfeature is providing multiple, redundant transducers on the multimodalbrain sensing lead for some or all of the different sensing modalities.This redundancy will allow an alternate transducer to be used if aprimary transducer fails and/or allows the best of two or moremeasurements for a given modality to be selected.

When one of the modalities provided in embodiments is voltammetry, thenanother robustness feature is a durable design for the voltammetryelectrodes. Traditional voltammetry electrodes for in vivo use are madeof a single carbon fiber extending from the tapered tip of a glassmicropipette. This traditional design can be quite fragile and thuslikely impractical or otherwise unsuitable for long term (chronic) use.Embodiments of the multimodal brain sensing lead that are configured forthe voltammetry modality may use the disk-shaped end of a glassy carboncylinder as a voltammetry electrode. Glassy carbon is extremely durableand suitable for a chronic recording application.

Alternatively, ultrananocrystalline diamond (UNCD) coated metal, whichis also very durable and suitable for voltammetry, may be used for thevoltammetry electrode.

Other features that may be provided according to embodiments for one ormore sensing modalities and which are expected to contribute torobustness and durability include electrical isolation of sensorcomponents from each other and from other elements of the leads (e.g.,conductors); and the use of non-corroding materials, hermetic seals andfeedthroughs. These features are elaborated upon in the descriptionbelow.

Miniaturized Sensors

The optical and microelectrode sensors described below and according toembodiments are highly miniaturized and designed to fit into the verylimited space available in an implantable lead. The optical sensorincludes two LEDs and a photodiode, each of which is specificallyselected, arranged and packaged so that they fit into a small space. Inan embodiment, the dimensions of this small space are approximately1.5×0.5×0.3 mm. The wiring that connects the sensor to the electronicsmodule is designed to accommodate the small space available andfacilitate manufacturing and assembly.

The microelectrode module has also been designed for manufacturabilityand for easy incorporation into the lead. This design is simple andelegant in that no welding of contacts is required. Especially inembodiments in which glassy carbon is used for a microelectrode, thismaterial cannot be welded because it is too hard and inert for welding.The microelectrodes are press fit through a hole in the side of a PEEKcylinder and the sharp metal tip of each microelectrode—for a glassycarbon microelectrode, this is the pointed end of the proximal end ofthe electrode (as will be described below)—penetrates and deforms ametal contact on the electronics module, thus making a secureconnection. An alternative to glassy carbon is ultrananocrystallinediamond-coated tantalum, platinum-indium, or other metal.

Multimodal Sensing

Embodiments are specifically designed for multimodal sensing. Multimodalsensing is the combined acquisition of two or more of: (1) neuronalfield potential measurements; (2) neuronal single unit activitymeasurements; (3) neuronal multi unit activity measurements; (4)rheoencephalography measurements; (5) neurochemical and pharmaceuticalvoltammetric measurements; (6) optical blood volume measurements; and(7) optical blood oxygenation measurements. Multimodal sensing isdesirable at least for the reason that it provides a more completedescription of physiological activity than is achievable with any singlemodality. Most diseases and disorders of the brain involve a combinationof abnormal neuroelectric, neurochemical, and hemodynamic activities.

Time Multiplexed Sensing

Embodiments are specifically designed for time multiplexed multimodalsensing. Time multiplexed sensing as used herein means the ability tocollect multiple modalities of information at or about the same time.Time multiplexed sensing may be a desirable alternative to same-timesensing, since some sensing modalities cannot be used simultaneously.For example, if one component (e.g., a physical element) used in a firstsensing modality is also used in a second sensing modality, thecomponent may have to be shared by different sensing modalities.

Modalities that may share one or more components with other modalitiesinclude voltammetry, neuronal single unit activity, and neuronal multiunit activity sensing modalities. A voltammetry modality may beconfigured to use the same microelectrodes as a single unit activitymodality and/or as a multi unit activity modality.

Additionally, time multiplexed sensing may be desirable to avoidsituations in which one sensing modality interferes with another sensingmodality or modalities. For example, if voltammetry and field potentialmeasurements were undertaken simultaneously, then the waveform used toacquire the voltammetry measurement may be reflected somehow in thefield potential measurement, such that the voltage changes sensed in thefield potential measurement would to some degree be sensed simplybecause the voltammetry measurement was being acquired. In other words,the voltammetry modality may cause voltage changes in the tissue thatwould interfere with field potential measurements if both thevoltammetry measurement and the field potential measurement wereacquired simultaneously.

Time multiplexed sensing also is important because the convergence ofinformation from multiple modalities over time is likely a betterdiagnostic indicator than information from any single modality.Depending on the specific combinations of sensing modalities, timemultiplexed sensing may be simultaneous or interleaved.

Embodiments of a multimodal brain sensing lead meet several technicalchallenges. Specifically, the method of making measurements using eachmodality satisfies the following requirements: (1) making a measurementusing one modality must not interfere with measurements of any othermodalities; (2) measurements from each different modality provided viathe lead must be made frequently enough to provide a clinically relevantdescription of ongoing physiological activity; (3) making measurementsfrom all modalities must use a minimum of electrical power, so thatbattery life is maximized; and (4) measurements from all modalities mustbe safe.

Localized Monitoring

The multimodal brain sensing lead is specifically designed for localizedmonitoring of multiple physiological variables. The multimodal lead thusprovides one way to monitor multiple modalities of physiologicalinformation at or about the same time from the same localized brainarea. In embodiments, sensors for multiple different modalities areplaced in close proximity to each other on the same probe or lead foroptimal localization of the measured data. Localized monitoring ofmultiple physiological variables is important for describingphysiological changes that are correlated in space as well as in time.

In addition to supporting chronic implantability, embodiments areprovided with multiple sensors for each sensing modality so that withina modality, the sensor with the best signal may be monitored, and sothat sensors in sub-optimal locations may be ignored. This redundancycan serve one or both purposes: (1) redundancy in case of failure and(2) selection of a sensor with the best signal. For example, under thecircumstances of a particular lead implant and depending, on the desiredsignals, measurements from sensors or transducers that are physicallysituated adjacent a blood vessel or in the fluid of a brain ventriclemay be sub-optimal. In this case, if an embodiment is provided withmultiple instances of for example, a voltammetry sensor, then ameasurement from a voltammetry sensor configuration not so close to theblood vessel may be preferred over a measurement from a voltammetrysensor configuration adjacent to the blood vessel. Additionally,embodiments with redundancy in the sensor configurations for a givenmodality may be leveraged in order to identify a location in thepatient's brain from which the most clinically relevant activity may bemeasured. For example, choosing the most clinically relevant sensorconfigurations to use for a given modality on a given lead may involvecomparing signals from sensor configurations for the same modality butlocated at different places along the same lead or located on differentleads altogether.

MRI Safety

Embodiments of the multimodal sensing brain lead incorporate featuresthat contribute to safety in an MRI field by minimizing the degree towhich components in the distal portion of the lead heat when the patientis subjected to magnetic resonance imaging. Heating in an implanted leadin an MRI field occurs because electromagnetic energy is absorbed bylong wires in the lead (e.g., conductors) and is converted to heat atthe macroelectrodes, which can damage brain tissue near themacroelectrodes. In some variations of implantable brain leads,electromechanical relays are used to physically disconnect themacroelectrode from the lead wires and prevent heating of themacroelectrodes and tissue damage. In embodiments of a multimodal brainsensing lead described here, an electronics module provided in the leadmay contain an omnidirectional magnetic field detector configured todetect when a sufficiently strong magnetic field with characteristicsindicative of an MRI system is present. When the MRI field is detectedby the omnidirectional magnetic field detector, then this detectioncauses microelectromechanical relays in the lead (e.g., in anelectronics module provided in the lead) to operate to disconnect thelead wires from the macroelectrodes. In this way, macroelectrode heatingdue to electromagnetic energy from an MRI system is discouraged.

Multimodal Depth Brain Sensing Lead

Gross Lead Dimensions

In one embodiment, the gross dimensions of an implantable multimodaldepth brain sensing lead are about 44 cm in length, and round in crosssection with a diameter of about 1.25 mm. However, it should beappreciated that the gross lead dimensions may be different than thosespecifically described herein. In one embodiment, the multimodal brainsensing lead consists of three major sections: a distal portion, whichis surgically implanted at a desired location within the brain; anelongated lead body, and a proximal portion, which may either beconnected to the housing of an internal host device implanted in thebody, preferably the cranium, or to an external host device outside thebody.

Proximal Portion of Multimodal Depth Brain Sensing Lead

The design of the proximal portion of the multimodal brain sensing leadfacilitates chronic implantability through reliable connections to theproximal lead contacts, secure electrical connections, good electricalisolation, and durable construction. FIG. 1 is a side, partial sectionalview of a proximal portion of a multimodal brain sensing lead 100, inaccordance with an embodiment. The proximal portion 100 includes leadwires or conductors 102, a length of polyimide tubing 104, proximal leadcontacts 106A, 106B, 106C, 106D, 106E, and 106F (hereinafter, “proximallead contacts 106”, unless otherwise noted), silicone spacers 108A,108B, 108C, 108D, 108E, and 108F (hereinafter, “silicone spacers 108”,unless otherwise noted), and a proximal end cap 110. In one embodiment,the number of lead wires or conductors 102 is six. In this embodiment,the six lead wires or conductors 102 are connected to the proximal leadcontacts 106 that are threaded onto the length of the polyimide tubing104 and separated from each other by the silicone spacers 108. Theproximal lead contacts 106 couple with electrical contacts on aconnector in the host device, facilitating the transfer of electricalsignals through the lead. Four of the lead wires or conductors 102 thatare connected to the four most distal lead contacts of the proximal leadcontacts 106 are used for neuronal field potential recording andelectrical stimulation, while the remaining two lead contacts of theproximal lead contacts 106 are used for the transmission of power anddigital communication.

FIG. 2 is a cross-sectional view and FIG. 3 is an end elevational viewof a proximal lead contact 106 of FIG. 1, in accordance with anembodiment. In one embodiment, the proximal lead contacts 106 are metalrings, made of a 90% platinum and a 10% iridium alloy (a.k.a. “PtIr”),that are about 1.5 mm long, with an outer diameter of about 1.25 mm andan inner diameter of about 0.9 mm. It should be noted, however, that themake up and dimensions of the proximal lead contacts 106 may have othermake ups and dimensions than that described herein. The inner and outeredges of the cylinder ends, in one embodiment, are beveled at 45 degreesfor about 0.025 mm. This sort of beveling eliminates sharp edges thatmight damage tissue, and facilitates over-molding of silicone betweenelectrodes. In one embodiment, each proximal contact 106 has a groovethat is about 0.10 mm wide and deep, and about 0.75 mm long that extendsfrom the outer edge of the distal contact end, and that extends towardsa proximal end of the proximal contacts 106. It should be noted that thegroove may have dimensions other than that described herein. The grooveis for attachment of a lead wire, such as lead wire or conductor 102.The proximal lead contacts 106 may be sequentially numbered 1-6 indistal-to-proximal order.

A multimodal brain sensing lead according to embodiments is formed froma length of polyimide tubing 104 that runs through the center of theproximal lead contacts 106 and silicone separators 108. The length ofthe polyimide tubing 104 may be about 23 mm long, 0.50 mm diameter, andcharacterized by a wall thickness of about 0.025. The polyimide tubing104 serves to stiffen the proximal lead end 100, insulate the inneraspect of the proximal lead contacts 106 and protect the inner aspect ofthe proximal lead contacts 106 from damage, for example, by a styletused to provide stiffness or rigidity to the lead while the lead isbeing implanted in the patient. It should be noted that the polyimidetubing 104 may be of any dimension that still enables the polyimidetubing 104 to function as described herein.

In one embodiment, five silicone spacers 108 separate six proximal leadcontacts 106 from each other. For example, each spacer may be about 1.5mm long and made of silicone that is molded over the lead wire(s) orconductor(s) 102 and polyimide tubing 108 and into the space between theproximal lead contacts 106. This silicone provides electricalinsulation.

FIG. 4 illustrates an enlarged side view of a proximal end cap 110 thatis also shown in FIG. 1, in accordance with an embodiment. The proximalend cap 110 may be press-fit into the proximal end of the most proximallead contact of the proximal lead contacts 106. In one embodiment, theproximal end cap 110 may be made of Ptlr and cylindrical with an innerdiameter of about 0.5 mm. In yet another embodiment, the proximal end ofthe proximal end cap 110 is about 1 mm long and 1.25 mm in diameter. Theouter proximal edge of the proximal end cap 110 is rounded. In oneembodiment, the distal end of the proximal end cap 110, which ispress-fit into the most proximal contact, is about 0.5 mm long and about0.9 mm in diameter.

Still referring to FIGS. 1-4, prior to lead implantation, in oneembodiment, a stylet is inserted through the hole in the proximal endcap 110 into the central lumen of the lead. The stylet provides supportfor the lead and makes it semi-rigid while it is implanted in the brain.The stylet is removed after the lead is stereotactically positionedwithin the brain.

In one embodiment, six lead wires or conductors 102 run the length ofthe lead body. Each lead wire or conductor 102 may be about 0.1 mm indiameter and made of multistranded PtIr wire. Each lead wire may becoated with insulation (e.g., a layer of ethylene tetrafluoroethyleneETFE) insulation), resulting in a somewhat greater overall diameter. Atthe proximal lead end 109, the lead wires or conductors 102 are threadedbetween the polyimide tubing 104 and the inside of the proximal leadcontacts 106. A proximal section of each lead wire of the lead wires orconductors 102 is stripped of insulation for about 0.5 mm, pressed intothe groove of a proximal lead contact of the proximal lead contacts 106,and laser-welded into place, according to an embodiment. Each lead wiremay be numbered 1-6 according to the proximal lead contact to which itis connected. At a distal portion of the lead, each lead wire 102 may belaser-welded to a connection point on an electronics module located in adistal portion of the lead according to an embodiment.

Lead Body

FIG. 5B is a cross-sectional view of a lead body 500 taken along theline A-A of FIG. 5A, in accordance with an embodiment. In oneembodiment, is a multi lumen tube of silicone with an outer diameter ofabout 1.25 mm. A central lumen 502 is about 0.5 mm in diameter. Sixsmaller lumens 504A, 504B, 504C, 504D, 504E, and 504F (hereinafter,“smaller lumens 504”, unless otherwise noted), each of about 0.2 mm indiameter, surround the central lumen 502, according to an embodiment.These smaller lumens are positioned about midway between an outer edge506 of the central lumen 502 and an outer edge 508 of the lead body 500,and are circularly arranged at 60 degree intervals around the center ofthe lead body 500. The six lead wires or conductors 102 run through thesix smaller lumens 504. A stylet may be inserted into the central lumen502 for use while the lead is being implanted in the patient and thenremoved. After the lead is implanted and the stylet has been removed,the central lumen 502 eventually fills with fluid. The multi lumendesign and insulated lead wires or conductors 102 facilitate chronicimplantability by providing good electrical isolation of the lead wires102. Providing lead wires or conductors 102 that are multistrandedcontributes to good durability.

Distal Portion of Multimodal Depth Brain Sensing Lead

FIG. 6 is a side, partial sectional view of a distal portion 600 of amultimodal depth brain sensing lead, according to an embodiment. Thedistal portion 600 includes: an electronics modules, including a firstelectronic module component 602A, a second electronics module component602B and a third electronics module component 602C (hereinafter,“electronics module 602”, unless otherwise noted) that connects to thesix lead wires 102 at a proximal portion 604 of the distal portion 600;three kinds of transducers for seven different sensing modalities;macroelectrodes 606A, 606B, 606C and 606D (hereinafter, “macroelectrodes606”, unless otherwise noted) for the field potential measurementmodality and the rheoencephalography measurement modality; opticalassemblies 610A and 610B (hereinafter, “optical assemblies 610”, unlessotherwise noted) for the optical blood volume and optical bloodoxygenation modalities; and a microelectrode assembly 614 for thevoltammetry modality the neuronal single unit activity measurementmodality and/or the neuronal multi unit activity measurement modality; adistal tip 612; and a distal end 608 of the distal portion 600.Together, the electronics module 602 and transducers service all of thesensing modalities.

FIG. 7 is an enlarged view of the electronics module 602 of FIG. 6, inaccordance with an embodiment. The electronics module 602 consists of amain body 6028, a proximal shaft 602A, and a distal shaft 602C. The mainbody 602B, the proximal shaft 602A, and the distal shaft 602C are madeof a nonconductive, biocompatible material, such as polyether etherketone (a.k.a. PEEK), according to an embodiment. The design of theelectronics module 602 is robust and durable, supporting chronicimplantation as well as the miniaturized multimodal sensors.

Referring still to FIGS. 1-7, in one embodiment, the main body 602B is aPEEK cylinder about 2 mm long and about 1.25 mm in diameter. It containselectronic circuits that support the multiple sensing modalities. Theseelectronics are hermetically packaged and connected via hermeticfeedthroughs to electrical contacts on the proximal shaft 602A and thedistal shaft 602A. Some specific electronics are described that may beused beneficially in embodiments are described below in the context ofthe methods used to acquire measurements for each sensing modality.

According to an embodiment, the proximal shaft 602A of the electronicsmodule 602 is a PEEK cylinder about 3 mm long and about 0.5 mm indiameter, extending proximally from the main body 602B of theelectronics module 602. The tip of the proximal shaft 602A is designedto be inserted about 1 mm into the central lumen 502 of the lead body500. In one embodiment, the tip may be adhered in place by silicone thatis molded around the portion of the proximal shaft 602A between the leadbody 500 and the main body 602B of the electronics module 602. Thesilicone also serves to electrically isolate the exposed ends of thelead wires or conductors 102 that are laser-welded to contacts on theproximal shaft 602A. There are six electrical contacts on the proximalshaft 602A, centered at about 0.3 mm intervals from each other, starting0.3 mm from the proximal end of the main body 602B. The electricalcontacts are also centered at about 60 degree intervals from each otherso that they are arranged in a spiral pattern along the proximal shaft602A.

The six lead wires or conductors 102 are connected to the contacts onthe proximal shaft 602A in the same proximal-to-distal order as they areconnected to the proximal lead contacts 106 on the proximal portion 100(of FIG. 1). That is, the most proximal contact on the proximal portion100 is connected to the most proximal contact on the proximal shaft 602Aof the electronics module 602, and so on and so forth. In an embodiment,the four most distal contacts are used for neuronal field potentialrecording. In some embodiments, where the multimodal brain sensing leadis also configurable to deliver a form of electrical stimulation to thepatient (in addition to sensing physiological information from thepatient), the four most distal contacts may also be used as electrodesthrough which electrical stimulation can be delivered, althoughtypically not at the same time as a given contact is being used forsensing. The two most proximal contacts may be used for power anddigital communication.

In an embodiment, the six lead wires or conductors 102 extend past theend of the multilumen tube of the lead body 500 for varying lengths ofabout 0.8 to 1.8 mm at about 0.3 mm intervals. Each lead wire orconductor 102 may be stripped of about 0.5 mm of insulation and theirends laser-welded to the electrical contacts on the proximal shaft 602A.Electrically conductive circuit paths within the proximal shaft 602Aconnect to the electronics package in the main body 60213. Their initialconnections may be to microelectromechanical relays (not shown) whichare controlled by electronic circuitry that detects an MM field anddisconnects the lead wires 102 from the macroelectrodes 606 to reducemacroelectrode heating by electromagnetic MRI energy.

FIG. 8 is an enlarged end view of the distal shaft 602C of theelectronics module 602 of FIG. 7. The distal shaft 602C may be formedfrom a PEEK cylinder about 15 mm long and about 0.5 mm in diameter thatextends distally from the main body 602B of the electronics module 602.At the locations where macroelectrodes and a microelectrode assembly arepositioned, there are four ridges, 802A, 802B, 802C, and 802D(hereinafter, “ridges 802”, unless otherwise noted). Each ridge may beabout 0.1 mm wide, about 0.18 mm tall and located at about 90 degreeintervals from each other, according to an embodiment. Each ridge of theridges 802 may be the same length as the macroelectrode ormicroelectrode assembly that fits over it. The ridges 802 serve to helpposition the macroelectrodes and microelectrode assembly duringconstruction of the lead.

Electrically conductive circuit paths extend from the electronicspackage through moisture-proof hermetic seals into the proximal shaft602A and the distal shaft 602C of the electronics module 602, andterminate in connection points for the attachment of lead wires orconductors 102, proximally, and macroelectrodes 606 (of FIG. 6),distally.

The transducers provided on a given instance of a multimodal brainsensing lead may include any or all the following: (1) macroelectrodes;(2) microelectrodes; (3) light emitters; and (4) photodetectors. Thedifferent sensing modalities use the different transducers as follows:(1) neuronal field potential measurements are made usingmacroelectrodes; (2) neuronal single unit activity measurements are madeusing microelectrodes; (3) neuronal multi unit activity measurements arealso made using microelectrodes; (4) rheoencephalography measurementsare made using macroelectrodes; (5) neurochemical and pharmaceuticalvoltammetric measurements are made using both macroelectrodes andmicroelectrodes; (6) optical blood flow and volume measurements are madeusing light emitters and photodetectors; and (7) optical bloodoxygenation measurements are also made using light emitters andphotodetectors.

FIGS. 9 and 10 are different views of a macroelectrode 606: FIG. 9 is aside, partial sectional view of a macroelectrode 606 and FIG. 10 is across-sectional view of a macroelectrode 606. In one embodiment, thereare five macroelectrodes on a distal portion 600 of the multimodal brainsensing lead. Each macroelectrode 606 may be identified by the number ofthe lead wire or conductor 102 to which it is connected. In anembodiment of a multimodal depth brain sensing lead, each macroelectrode606 is a PtIr ring with an outer diameter of, about 1.25 mm, and aninner diameter of about 0.9 mm. Four of the macroelectrodes are about 2mm long and used for neuronal field potential measurements,rheoencephalography measurements and delivering electrical stimulation,according to an embodiment. The fifth macroelectrode is about 1.5 mmlong and is used as a counter or reference electrode for voltammetry andmicroelectrode recording, according to an embodiment. Eachmacroelectrode 606 may have a groove that is about 0.1 mm wide and deepand about 0.375 mm long that extends from the outer edge of the distalcontact end, and towards the proximal end of the contact.

In some embodiments, macroelectrodes 606 are assembled onto the distalshaft 602C of the electronics module 602 in two steps. First, one end ofan about 2 mm long, 0.1 mm diameter Par wire is laser-welded into thegroove in a macroelectrode 606. Then the macroelectrode 900 is threadedonto the distal shaft 602C, groove first, and the other end of the wireis laser-welded to a contact point on the distal shaft 602C. Then themacroelectrode 900 is pushed over the welded contact on the distal shaft602C and the wire is drawn tight. Silicone is injected into the spaceflanking each macroelectrode 606, also filling the space between theinside of each macroelectrode 606 and the distal shaft 602C.

FIGS. 11A and 11B are views of a microelectrode assembly 614 of FIG. 6,in accordance with an embodiment. A microelectrode assembly 614 existson the distal portion 600 of the multimodal brain sensing lead.Microelectrodes may be used for making neuronal single unit activity andneuronal multi unit activity measurements as well as for makingvoltammetry measurements. A microelectrode assembly 614 may consist of aring-shaped assembly body 1102 with four cylindrical microelectrodes,1104A, 11048, 1104C, and 1104D (hereinafter, “microelectrodes 1104”,unless otherwise noted) embedded into its surface. The assembly body1102 is made of a nonconductive, biocompatible material, such as PEEK,and is about a 1.5-mm long cylinder with an outer diameter of about 1.25mm and an inner diameter of about 0.6 mm, in accordance with anembodiment. There may be four grooves, 1106A, 11068, 1106C, and 1106D(hereinafter, “grooves 1106”, unless otherwise noted) in the inside ofthe cylinder at about 90 degree intervals from each other. Each grooveof the grooves 1106 may be about 0.15 mm wide and 0.15 mm deep. Thegrooves fit over the ridges on the distal shaft 602C of the electronicsmodule 602 and aid in positioning of the microelectrode assembly 614during lead construction.

The microelectrodes 1104 may be made of a biocompatible materialsuitable for both voltammetry and neural (single or multi) unit activityrecording, such as glassy carbon. Alternatively, a material such astantalum coated with ultrananocrystalline diamond may be used. A typicalmicroelectrode 1104 may be about 0.425 mm long and about 0.1 mm indiameter, with one pointed end, in one embodiment. The microelectrodes1104 are positioned midway between the two ends of the assembly body1102 and arranged circularly around its perimeter at about 90 degreeintervals, midway between the grooves, in one embodiment. The taperedend of each microelectrode of the microelectrodes 1104 is pressed intoabout a 0.1 mm hole in the assembly body 1102 so that the outer end ofthe microelectrodes 1104 are flush with the outer surface of theassembly body 1102, in accordance with an embodiment. Eachmicroelectrode of the microelectrodes 1104 may be located directly overan electrical contact point on the distal shaft 602C. When themicroelectrode is pressed into its hole, it slightly deforms thecontact, making a secure electrical connection.

FIG. 12 illustrates a cross-sectional view of the optical assemblies 610of FIG. 6, in accordance with an embodiment. There may be two or moreoptical assemblies 610 on a distal portion 600 of a multimodal brainsensing lead according to embodiments, and the optical assemblies may besubstantially identical in terms of the components used in the same orthey may have different types of components or components with varyingspecifications (e.g., the wavelengths of the LEDs may differ fromoptical assembly to optical assembly). Each optical assembly 610 mayconsist of a cylindrical lens 1202 surrounding two optoelectronicpackages, 1204A and 1204B (hereinafter, “optoelectronic packages 1204”,unless otherwise noted), according to an embodiment. In one embodiment,the lens is about 1.5 mm long, with an outer diameter of about 1.25 mmand an inner diameter of about 0.5 mm, and made of a clear biocompatibleepoxy. Additionally or alternatively, the optical assembly 610 may becoated with sapphire to provide a hermetic seal around the electronics.

The two optoelectronic packages 1204 desirably are arranged on the leadso that they are roughly parallel to each other and 180 degrees fromeach other around the distal shaft 602C of the electronics module 602,in accordance with an embodiment.

In one embodiment, each optoelectronic package is about 1.5 mm long,about 0.5 mm wide and about 0.3 mm thick. In yet another embodiment,each optoelectronic package contains two LEDs (an LED 1206C is labeledin FIG. 12), preferably an 805 nm LED and a 630 nm LED, and aphotodetector (a photodetector 1206D is labeled in FIG. 12) sensitive toboth LED wavelengths. For a given application of a multimodal brainsensing lead, the wavelengths of the LEDs may be selected for makingeffective blood volume and oxygenation measurements. The electronics aremounted onto a ceramic base 1206. Each optoelectronic package 1204A and1204B shown in FIG. 12 is provided with four electrical contacts,including an electrical contact for the positive contact of each LED andthe photodiode and for a common ground. The electrical contacts may beconnected via 0.100 mm PtIr wires 1208 to electrical contacts 1210 onthe distal shaft 602C. The optoelectronic packages 1204 preferably aremade moisture-proof and are hermetically sealed by encasing them in ametal electronics package with a glass window above the optical elementsand glass feedthroughs for the wires connecting to the distal shaft 602Cof the electronics module 602. The lens epoxy insulates the wiresconnecting the optoelectronics module to the distal shaft 602C.

FIG. 13 is a view of a distal tip 612 (also shown in FIG. 6). In thisembodiment, the distal tip 612 of the lead is cylindrical with a totallength of about 1.625 mm and a rounded end. It is made of PEEK. Theproximal 1 mm or so of the distal tip 612 has a diameter of about 0.9mm, while the distal 0.625 mm or so of the distal tip 612 has a diameterof about 1.25 mm and is hemispherically shaped to facilitate bluntdissection and avoid puncturing blood vessels as it is inserted into thebrain. The proximal 1 mm or so of the distal tip 612 may be press-fitinto the most distal macroelectrode contact.

Multimodal Strip Brain Sensing Lead.

The foregoing discussion is directed primarily to a multimodal brainsensing lead the distal portion of which is intended to be used as adepth lead or deep brain lead, that is, the distal portion is intendedto be implanted into neural tissue of a patient's brain. In a depthlead, components (such as transducers) used to acquire measurements fora given sensing modality may be oriented to best suit the in-brainimplant location.

For example, a macroelectrode may comprise a ring electrode such that aconductive surface of the electrode is exposed to the tissue all aroundthe circumference of the distal portion of the lead. An optical sensormay be configured so that an illuminating element, a light-receivingelement and/or a lens is oriented in a particular direction relative tothe distal shaft of the lead. A strip lead is designed to rest on asurface of the patient's brain rather than to be implanted into thebrain tissue. Accordingly, a component of a sensing modality may beoriented differently than in a depth lead application, so as to bestacquire the physiological data from the patient.

For example, whereas a macroelectrode may be in the form of a ring orcylindrical electrode on a depth lead, in a strip lead configuration,the macroelectrode may be in the form of a disk the conductive surfaceof which is designed to rest against a surface of the brain when thedistal portion is implanted. Thus, the macroelectrode is provided in thestrip lead so that it is configured to be receptive only to the regionof brain tissue underneath it, and not to the opposite-facing surface(i.e., the surface of the macroelectrode facing out towards the skull).

The selective receptiveness of the macroelectrode may be accomplishedusing insulation. The multimodal strip lead may be configured to haveeach or all of the same sensing modalities as a multimodal depth brainsensing lead. It will be appreciated that one or more components of eachsensing modality might be implemented differently, for example, in termsof conductive surfaces or orientation, to optimize the modality for thestrip lead application.

Proximal Portion of Multimodal Strip Brain Sensing Lead

The proximal portion of a multimodal strip brain sensing lead may beconfigured in substantially the same way as the proximal portion of amultimodal depth brain sensing lead, for example, where the device whichis acquiring the measurements from each sensing modality and to whicheach lead is to be connected are the same. ID the embodiments of amultimodal strip brain sensing lead described herein, for example, theproximal portion is identical to the to the proximal portion 100 of themultimodal depth brain sensing lead of FIG. 1.

Distal Portion of the Multimodal Strip Brain Sensing Lead

FIG. 14 is a bottom view of a distal portion of a multimodal stripsensing lead, in accordance with an embodiment. FIG. 15 illustrates aside, partial sectional view of the distal portion 1400. The distalportion 1400 consists of a flattened piece of silicone containing aplurality of sensor components (e.g., transducers). More specifically,the distal portion 1400 includes an electronics module 1402, avoltammetry ground/reference 1404, macroelectrodes 1406A, 1406B, 1406Cand 1406D, a first optical assembly 1408A and a second optical assembly1408B, and a microelectrode assembly 1410. A distal shaft of theelectronics module 1402 (shown in FIGS. 14 and 15) is similar to thedistal shaft of the multimodal depth brain sensing lead described above,but in the strip lead, the electronics module 1402 is configured in away that encourages the strip to remain flexible (e.g., floppy) and tolay approximately flat upon implantation.

Measurement Acquisition

In embodiments, acquiring a measurement from a plurality of sensingmodalities may involve several steps. Before any measurements can beacquired, the sensor must be configured appropriately. For fieldpotential measurements, single unit neuronal activity recording andneuronal multi unit activity recording, electrophysiological sensing,electrodes, amplifier gain and filter settings, and sampling rate mustbe selected. For the optical sensing modalities (i.e., optical bloodvolume and optical blood oxygenation measurements), LEDs,photodetectors, brightness, gain, integration time, and sampling ratemust be selected. For the voltammetry modality, voltage waveforms andscan rates must be selected. For the rheoencephalography modality,electrodes, waveforms, and scan durations must be selected.

Once the sensing modalities (and associated components of each) havebeen initially configured, and then acquiring measurements from eachmodality may be accomplished in accordance with a timing schedule. Whenacquisition of a measurement is triggered pursuant to the timingschedule, the measurements are collected, digitized and stored in thehost device.

Referring now to FIG. 20, a host device 2006 (e.g., an implanted medicaldevice) may be configured to receive the data acquired from the sensingmodalities of the multimodal brain sensing lead through a sensorinterface 2100. (In FIG. 20, four sensors 2018A, 2018B, 2018C, and 2018Drepresent the one or more sensing modalities implemented in one or moreinstances of a multimodal brain sensing lead). The sensor interface 2100may be configured to subject the acquired data to subsequent signalprocessing (e.g., amplification, filtering, and other smoothing ofwaveforms, etc.).

The data may also be operated on by one or more algorithms running inthe host device, for example, in control module 2008 including adetection subsystem 2102 and controlled by a CPU 2110, such as a patternor feature detection algorithm or a time-dependent detection algorithmor another algorithm that looks for certain predefined “events” orsequences of events in a measured signal, including but not limited to astate-detection algorithm. The output of a detection algorithm oralgorithms can be used as part of a closed-loop system, for example, viaa communications subsystem 2108, to trigger delivery of a therapy suchas electrical stimulation. Examples of detection algorithms that may beused in connection with an implantable medical device receiving signalssensed from brain leads are described in, for example, U.S. Pat. No.6,810,285 to Pless et al. for “Seizure Sensing and Detection Using anImplantable Device” issued Oct. 26, 2004 and U.S. Pat. No. 7,341,562 toPless et al. for “Modulation and Analysis of Cerebral Perfusion inEpilepsy and Other Neurological Disorders” issued Mar. 11, 2008. Each ofU.S. Pat. Nos. 6,810,285 and 7,341,562 are hereby incorporated byreference in the entirety.

A host device 2006 further may include a memory subsystem 2104 forrecording and/or storing (permanently or temporarily) informationobtained from the sensors or about a condition of the device (e.g.,remaining battery life). The host device may include a power supply2106, such as a primary cell or rechargeable battery, and a clock supply2112 to provide timing signals for, e.g., acquiring measurements fromthe various sensing modalities implemented on a multimodal brain sensinglead.

FIG. 17 is a schematic diagram of one example of a closed-loop systemwith which a multimodal brain sensing lead according to embodiments maybe beneficially used. Multimodal data acquisition 1802 based onphysiological signals 1804 sensed from the patient's brain 1806 madepossible by the multimodal brain sensing lead(s) are transmitted in theform of multimodal data 1808 to a detection algorithm or algorithms 1810running in a host device (such as another implanted component of theimplantable medical device system that includes the multimodal brainsensing lead(s)). Each detection algorithm 1810 runs according toparameter values that may be programmed in advance for the algorithm orcalculated in real time. The output of a detection algorithm 1810 may bedetected event(s) or state(s) 1820 which are provided as the input toone or more therapy algorithm(s) 1822. Each therapy algorithm 1822 mayalso run according to parameter values that may be preprogrammed orcalculated in real time, depending on the particular application of themedical device system. A therapy algorithm 1822 may cause a therapy(e.g., in the form of a burst or bursts of pulsatile electricalstimulation or in the form of a bolus of a drug) to be delivered 1824 tothe brain 1806 in response to the detection algorithm(s) 1810 and themultimodal data 1808 acquired from the multimodal brain sensing lead.

The host device may also have the capacity to store data acquired fromthe sensing modalities via the multimodal brain sensing lead, forexample in one or more areas of memory 2104 in the host device 2006.

Referring now to FIG. 19, if the host device is, like the multimodalbrain sensing lead, an implantable component of an implantable medicaldevice system, the host device may be configured to communicate with oneor more external components via a wireless communications link (such asa form of telemetry). The communication may be bidirectional, so that anexternal component (e.g., a physician's “programmer”) can be used toprogram the host device and/or to initially configure each sensingmodality prior to data acquisition from the patient (e.g., to setamplifier gains and sampling rates) and so that one or more types ofexternal components (e.g., the physician's programmer and a patient“remote monitor”) may be used to download data from the implanted hostdevice and subsequently store it on the external component. In FIG. 19,represented schematically are four physician programmers, namely,programmers 2020A, 2020B, 2020C, and 20201) and a patient remote monitor2026.

In some implantable medical device systems, the external components maybe configured to interface with one or more networks (a network 2022 isshown in FIG. 19) and/or a centralized database which is used forstoring data acquired from the sensing modalities and/or initialsettings for each sensing modality (a database 2028 is shown in FIG.19). Data may be transmitted from an external component through atelephone or broad band connection to a central database. Communicationwith a database may also be accomplished over the internet via a securewebsite.

A display provided on an external component such as a programmer or awebsite may be used by a patient's physician or other caregiver toreview and manipulate data acquired from each sensing modality. Forexample, a programmer or website may be used by a physician to look atdata acquired from each of a plurality of sensing modalities from agiven patient at or about the same time.

FIG. 16 is an example of a display that might be provided to a user on aprogrammer or over a secure website corresponding to data acquired fromdifferent sensing modalities of a multimodal brain sensing leadaccording to embodiments over time. More particularly, FIG. 16 is adisplay with a series of five graphs 1602, 1604, 1606, 1608, and 1610.Each graph corresponds to a single period of data acquisition in days.The first graph 1602 corresponds to a field potential measurementacquired using a field potential measurement modality implemented withcomponents on a multimodal brain sensing lead; the second graph 1604corresponds to a single unit activity/multi unit activity measurementacquired using either a single unit activity measurement or a multi unitactivity modality implemented with components on the same multimodalbrain sensing lead; the third graph 1606 corresponds to an optical bloodflow measurement acquired using an optical measurement modality (e.g.,optical blood volume measurement modality or optical blood oxygenationmeasurement modality) implemented with components on the same multimodalbrain sensing lead; the fourth graph 1608 corresponds to voltammetrymeasurement (of serotonin concentration) acquired using a voltammetrymeasurement modality implemented with components on the same multimodalbrain sensing lead; and the fifth graph 1610 corresponds to arheoencephalography measurement acquired using a rheoencephalographymodality implemented with components on the same multimodal brainsensing lead.

The ability to visualize data acquired from different sensing modalitiesfrom a common location in the patient's brain at or about the same timewill be clinically useful for evaluating such things as the status of apatient, the patient's response to a therapy, such as a therapy thatmight be delivered by a host device or another implantable component ofan implantable medical device system that includes the multimodal brainsensing lead, or other therapies the patient may be receiving.

Electrophysiological Recording Example

In this example, a multimodal brain sensing lead is surgically implantedwith its distal end oriented towards or in a hippocampal region of ahuman patient. The hippocampus is selected because the patient hasepilepsy with seizures originating in the hippocampus, and abnormalelectrographic activity, including electrographic seizures andinterictal discharges, is expected to be observed in the hippocampus.Neuronal field potential, neuronal single unit activity, and neuronalmulti unit activity measurement acquisition is configured with theobjective of recording neuronal activity for diagnostic and therapeuticpurposes. Diagnostic use includes recording and storing measurements ofneuronal activity for later review by a clinician. Therapeutic useincludes automatic analysis of neuronal activity measurements bycomputational algorithms in the host device, and subsequent therapydelivery. This analysis is performed in a closed-loop manner todetermine when therapy, for example, electrical stimulation, should bedelivered. Thus far, this scenario is similar to that used for neuronalfield potential recording by the responsive neurostimulation systemsunder investigation by NeuroPace, referred to as the “RNS SYSTEM”. Fieldpotential recording from implanted electrodes also is described in U.S.Pat. No. 6,016,449 to Fischell et al. for “System for Treatment ofNeurological Disorders” issued Jan. 18, 2000, as well as in U.S. Pat.No. 6,810,285. Both of U.S. Pat. Nos. 6,016,449 and 6,810,285 areincorporated by reference in the entirety herein.

Field Potential Measurement Acquisition

In an embodiment, a field potential recording is configured by adjustingthe settings for field potential amplification and analog-to-digitalconversion in a host device, such as an implanted responsiveneurostimulator configured for acquiring measurements from two or moreof the different sensing modalities of the multimodal brain sensinglead. This initial configuration is performed by a clinician usingsoftware implementable on an external device such as a general purposecomputer (e.g., laptop or handheld computer), which is designated a“programmer”. Software miming on the programmer is specifically designedto provide the user with a graphical user interface to communicate withand configure the host device and one or more multimodal brain sensingleads (e.g., a depth lead and a strip lead, or two depth leads, or twostrip leads) or some other combination of three or more multimodal brainsensing leads).

In this example, the system is configured so that field potentialmeasurements are acquired on two channels of the host device. The firstfield potential measurement channel will be used to sense things such asfield potential spikes, waves and oscillatory activity from neurons neara pair of macroelectrodes on the multimodal brain sensing lead. Thischannel is configured for differential recording. First, one of twoamplifiers in the host device is selected for field potential recording:for the purposes of this example, the selected amplifier will bedesignated the first amplifier and the other of the two amplifiers willbe designated the second amplifier. Next, input sources for theamplifier in order to acquire the differential measurement are selected:in this example, the input sources comprise three macroelectrodeslocated on the distal portion of a multimodal brain sensing lead and aconductive housing provided for the host device (e.g., the housing of animplanted responsive neurostimulator). For one differential measurement,a pair of adjacent macroelectrodes is selected as input sources. Morespecifically, a first macroelectrode is selected as the input and asecond macroelectrode as the reference for the first field potentialamplifier. These electrodes are selected because they are adjacent toeach other on the lead and field potential information from the neuronsin the vicinity of the first and second macroelectrodes is desired.Selection of a pair of electrodes is commonly used for differentialrecording. Differential mode is selected because a field potentialsignal describing differences between neural activities at twomacroelectrodes is desired. This signal will reflect primarily activitynear the electrodes and subtract out background activity common to bothelectrodes.

Next, filter settings are selected. For the purposes of this example, itis assumed that the first channel will be used primarily for recordingin the standard delta to gamma EEG frequency range, approximately 3 to100 Hz. Accordingly, a high-pass filter associated with the channel maybe set at 1 Hz, and a low-pass filter at 100 Hz. These settings aretypical for field potential recording. A notch filter is not enabled inthis particular circumstance because power line noise is not expected tobe a problem. A notch filter may be enabled later if noise isencountered.

Next, a gain setting is selected. For the purposes of this example, forthe first channel, a gain of 100 is selected because field potentialvoltage spikes of approximately ±10 mV are expected. This will result inapproximately ±1 V output from the amplifier. This is within theamplifier's dynamic range, assuming the amplifier is powered with 3.5 V,which is typical of implanted devices.

Finally, a sampling rate is selected. This is the rate at which theanalog-to-digital converter converts voltage measurements to digitalvalues. A sampling rate of 250 samples per second is selected. Thissampling rate is sufficient for EEG field potential recording in the3-100 Hz range.

The second field potential measurement channel will be used for singleended DC recording (as distinguishable from a differential recordingmode). Particularly in an application where a multimodal brain sensinglead is used to acquire localized information from a patient withepilepsy, single ended DC recording is desirable because DC voltagechanges may be associated with seizures and seizure onsets and are notdetectable with differential recording. First, an amplifier, input andreference are selected for field potential recording. The clinicianselects the second field potential measurement amplifier in the hostdevice with the third macroelectrode selected as an input, and theconductive housing of the host device, which serves as a patient ground,selected as a reference. Using a macroelectrode on the distal portion ofan implanted lead and patient ground as the amplifier inputs is commonfor single ended DC recording. The third macroelectrode is selected asthe input because low frequency voltage change information is desiredfrom the brain area in the vicinity of the electrode. The host devicehousing is selected as the reference because its large surface areamakes it a good source for patient ground.

Next, filter settings are selected. The second field potentialmeasurement channel will be used for recording DC and very lowfrequency. Thus, for the purposes of this example, a high-pass filter isset at either DC (no filter) or the lowest available frequency setting(which may be about 0.01 Hz). DC (no filter) is selected if a constantmeasurement of DC offset is desired, while a low frequency filtersetting is selected if only measurement of transient DC shifts isdesired. A low-pass filter is set at the lowest available setting (whichmay be about 10 Hz). This setting of the low pass filter generally willbe satisfactory for low frequency field potential recording in the rangeof 0-10 Hz. Again, in this example, a notch filter is not enabledbecause power line noise is not expected to be a problem. A notch filtermay be enabled later if noise is encountered.

Next, a gain setting is selected. For this second field potentialmeasurement channel, a gain of 10 is selected because the DC baselineshifts associated with seizure onsets and changes in cerebral blood floware expected to be relatively large. A gain of 10 will keep the ±175 mVfield potential EEG changes within the dynamic range of the amplifier,assuming a 3.5 V power supply.

Finally, a sampling rate is selected. A sampling rate of 10 samples persecond is selected because field potential EEG baseline voltage changesare expected to be relatively slow, and because this slow sampling ratewill allow power to be conserved by using a low duty cycle for theamplifier and analog-to-digital converter.

After the first and second amplifiers for each of the two fieldpotential measurement channels are initially configured by the user,measurement acquisition may be performed automatically according to adata acquisition timing schedule. Alternatively, measurement acquisitionmay be initiated manually by the user.

When a field potential measurement is acquired, each field potentialmeasurement amplifier and its associated analog-to-digital converter(ADC) are powered on. The amplifier is allowed to warm up and stabilizefor a few milliseconds, and then the signal is digitized at the samplingrate that was selected by the user when the field potential measurementamplifiers were initially configured. Digitized field potentialmeasurement voltage values are then stored in memory for subsequentanalysis and transmission outside the host device into an externaldatabase. In an embodiment, for field potential recording, each of theamplification, analog-to-digital conversion, and data storage occurwithin the host device.

Neuronal Single Unit Activity (SUA) and Neuronal Multi Unit Activity(MUA) Measurement Acquisition

In an embodiment, either of the modalities for neuronal single unitactivity measurement and neuronal multi unit activity measurement can beconfigured by adjusting the settings for amplification andanalog-to-digital conversion in the multimodal brain sensing lead usingsoftware in an external component (such as a programmer). A singleamplifier channel can be configured for combined single unit activitymeasurements and multi unit activity measurements. A differentialamplifier in the electronics module of the lead is used for single unitactivity and multi unit activity sensing. Electronics in the lead likelywill be needed for single unit activity and multi unit activityrecording (measurement) because there is no direct wire connectionbetween individual microelectrodes and the proximal portion of themultimodal brain sensing lead. There is also one macroelectrode used forvoltammetry and single unit activity and multi unit activity recordingthat is only connected to the electronics module. Because of this,single unit activity and multi unit activity electrodes are connected toan amplifier in the electronics module, the amplifier output isdigitized by an analog-to-digital converter in the electronics module,and the digitized output signal is transmitted to the host device whichis connected to the proximal portion of the lead. Subsequent signalprocessing and data storage then can be accomplished in the host device.

In this example, two channels are configured for use in recording(measuring) either single unit activity or multi unit activity (or bothat the same time) from the patient. The first single unit activity/multiunit activity channel is configured for differential recording. Thisfirst channel will be used to look for differential single unit activity(or multi unit activity as the case may be) such as in the form of spikewaveforms from single neurons (or local populations made up of multipleneurons). First, one of two amplifiers in the electronics module of thedistal portion of the multimodal brain sensing lead is selected forsingle unit activity recording (or multi unit activity recording): forthe purposes of this example, the selected amplifier will be designatedthe first amplifier and the other of the two amplifiers will bedesignated the second amplifier for single unit activity/multi unitactivity recording.

Next, input sources are selected for the amplifier. A pair of electrodesis selected as input sources. A first microelectrode is selected as theinput and a second microelectrode is selected as a reference for thefirst single unit activity/multi unit activity amplifier. These firstand second microelectrodes are selected because they are adjacent toeach other on the multimodal brain sensing lead and single unitactivity/multi unit activity information from the neurons in thevicinity of the first and second microelectrodes is desired. Selectionof a pair of electrodes is commonly used for differential recording.Differential mode is selected because a signal describing differencesbetween neural activities at two microelectrodes is desired. This signalwill reflect primarily activity near the electrodes and subtract outbackground activity common to both microelectrodes.

Next, filter settings are selected. This channel will be used primarilyfor recording extracellular neuronal action potential waveforms, whichhave high frequency content, approximately 100-5000 Hz. A high-passfilter is set at 100 Hz, and the low-pass filter is set at 5000 Hz.These settings are typical for single unit activity and multi unitactivity recording. The notch filter is not enabled because power linenoise is not expected to be a problem. It may be enabled later if noiseis encountered. Next, a gain setting is selected. For this channel, again of 100 is selected because the single unit activity and multi unitactivity voltage spikes of approximately ±10 mV are expected. This willresult in approximately ±1 V output from the amplifier. This is withinthe amplifier's dynamic range, assuming the amplifier is powered with3.5 V, which is typical of implanted devices.

Finally, a sampling rate is selected. This is the rate at which theanalog to digital converter converts voltage measurements to digitalvalues. A sampling rate of 5000 samples per second is selected. Thissampling rate is sufficient for single unit activity and multi unitactivity recording in the 3-100 Hz range.

Continuing with the example, a second single unit activity/multi unitactivity channel will be used for single ended recording between amicroelectrode and fifth macroelectrode which is connected to theelectronics module of the multimodal brain sensing lead. This channel isconfigured identically to the first single unit activity/multi unitactivity channel, with the exception of electrode inputs to theamplifier, which are a third microelectrode and the aforementioned fifthmacroelectrode. The macroelectrode provides a relatively stablebackground reference voltage that is subtracted from the microelectrodesignal, resulting in measurements that mainly reflect single unitactivity (or multi unit activity as the case may be) at themicroelectrode.

Optical Measurement Acquisition

In an embodiment, optical blood volume measurements and optical bloodoxygenation measurements are acquired using the multimodal brain sensinglead for such purposes as estimating blood flow, blood oxygenation,blood pressure, heart rate, and breathing rate. When a measurement ismade, a light emitting diode (LED) is illuminated and a photodiode (PD)is used to measure light reflected from the illuminated tissue. Thephotodiode output is amplified, digitized, and transmitted to the hostdevice. Several parameters are configured based on empirical testing inorder to optimize clinical utility. These include the following:selection of the LED and photodiode; LED brightness; photodiodeamplification; and analog-to-digital converter sampling rate. The LEDand photodiode are selected to ensure that the signal comes from thetissue of interest and any artifacts are minimized

For some measurements, such as blood oxygenation measurements, two LEDseach with different wavelengths may be illuminated alternately. LEDbrightness is adjusted to maximize signal to noise, make optimal use ofthe photodiode's dynamic range, and minimize power consumption.Amplification of the photodiode output may require a long integrationtime, which will limit the sampling rates available. Integration timeand sampling rate are selected based on the physiological parameterbeing measured. For example, blood flow and blood oxygenation changeslowly, so a low brightness, low sampling rate (e.g., 1 Hz) and a longintegration time (e.g., 1 second) may be used. Heart rate is much fasterand thus many samples per cardiac cycle (e.g., 10-100 samples persecond) may be required to reconstruct a cardiac waveform. Bloodpressure and breathing rate may also be determined by evaluation ofcardiac waveform data.

Even though multiple physiological variables are measured by opticalsensing, the basic measurement process is the same for each variable. Anindividual measurement is made in the following manner First, based on apre-determined timing schedule, a host device instructs the electronicsmodule of the multimodal brain sensing lead to illuminate a specific LEDat a specific intensity. Next, the host device sends a signal to anamplifier in the electronics module to connect to a specific photodiodein the lead. Finally, the host device instructs the amplifier and theanalog-to-digital converter in the multimodal brain sensing lead toamplify and digitize the light received by the photodiode for a selectedintegration time. After the integration period, the LED is powered downand illumination is stopped. The digitized light level is then sent fromthe electronics module to the host device for signal processing. Thisprocess is repeated for each measurement.

Multiple physiological variables can be measured at the same time byinterleaving the acquisition of multiple optical signals. Measurementsfor individual physiological variables can then be derived from themultiple signals.

Multiple optical signals are acquired using several differentcombinations of LEDs and photodiodes. This is done by collecting datafrom each photodiode in combination with each LED and comparing thesignals.

In an example, a multimodal brain sensing lead is provided with fouroptical assemblies, namely, a first, a second, a third, and a fourthoptical assembly. The first and second optical assemblies are providedon the lead more distally than are the third and fourth opticalassemblies. The first optical assembly is provided so that it isback-to-back with the second optical assembly (i.e., so that the firstoptical assembly is pointed about 180 degrees away from the secondoptical assembly relative to the circumference of the depth lead). Thethird optical assembly is also provided so that it is back-to-back withthe fourth optical assembly. The first and third optical assemblies areoriented on the lead so that they point in the same direction. Thesecond and fourth optical assemblies are oriented on the lead so thatthey point in the same direction, which may be a different directionthan the direction in which the first and third optical assembliespoint. Each of the four optical assemblies is provided with a photodiodeand two LEDs, each LED characterized with a different wavelength. In oneexample, the wavelengths for the two LEDs in each of the opticalassemblies are 805 ran and 630 nm.

For data acquisition from the first optical assembly, data samples areacquired using the photodiode in combination with the two LEDs ofdifferent wavelengths. The two LEDs are used together so that tissueoxygenation measurements based on the ratio of the two wavelengths maybe calculated. The two LEDs are alternately illuminated at moderateillumination intensity for duration of 16 ms each, or 31.25 samples persecond for each wavelength for 15 seconds. Then the same timing patternis used to collect samples using the second optical assembly, followedby the third optical assembly, followed by the fourth optical assembly.The cycle is repeated every minute. These results in eight signalscorresponding to light emitted from each of the LEDs in each of the fouroptical assemblies. Each signal consists of a repeating pattern of 15seconds of data samples followed by a 45-second pause. FIG. 18 is anexample of the sort of repeating pattern that might be used to acquiredata from a set of four optical assemblies implemented in a multimodalbrain sensing lead and processed by a host device, according to anembodiment. Each column in FIG. 18 represents one second. Each row inFIG. 18 indicates which photodiodes and LEDs of which of the fouroptical assemblies are active during that second. The pattern repeatscontinuously until stopped by the host device.

Optical data samples may be transmitted to the host device where theymay be stored in data files on the host storage medium, which may be RAMmemory or a hard drive.

The host device also may be configured to derive time seriesmeasurements of heart rate, respiratory rate, blood pressure, bloodoxygenation and blood flow from the optical data samples using variousalgorithms Examples of these algorithms include the following.

Heart rate may be derived from any of the eight signals by identifyingpeaks in the signal and calculating the interval between peaks inminutes. The reciprocal of this is the heart rate in beats per minute.

Breathing causes a low frequency modulation of the optical cardiacwaveform. Respiratory rate may be derived from any of the eight signalsby filtering out the heart rate signal, finding the respiratory peaks inthe filtered signal, and calculating the interval between peaks inminutes. The reciprocal of this is the respiratory rate in breaths perminute.

Blood pressure may be derived from any of the eight signals by measuringthe difference between the optical cardiac waveform maximum during acardiac cycle and the previous minimum. This difference is proportionalto blood pressure and may be converted to blood pressure usingpreviously collected calibration values. Alternatively or additionally,the systolic and diastolic blood pressures can be estimated from thesystolic upstroke time and diastolic time in the optical cardiacwaveform after application of calibration values.

Blood oxygenation may be derived from any pair of interleaved signalsfrom the two LEDs of a given optical assembly on a multimodal brainsensing lead by calculating the ratio of these two signals and applyingpreviously collected calibration values.

Blood flow and blood volume may be derived from any of the eight signalsby calculating the average light intensity over several cardiac cycles.This value is proportional to the volume of blood in the illuminatedtissue.

Voltammetry Measurement Acquisition

In an embodiment, voltammetry measurements are acquired using themultimodal lead for the purpose of estimating the concentration ofoxidizable and reducible chemicals in the brain such as drugs (L-DOPA),neurotransmitters (dopamine, serotonin, glutamate, GABA), and otherchemicals (hydrogen, oxygen). An example for clinical depression is thedepression-related neurotransmitter serotonin and the drug fluoxetineProzac). An example for movement disorders is the Parkinson's diseaserelated neurotransmitter dopamine and the drug levodopa (e.g. Sinemet).

Voltammetry measurements may be acquired from the multimodal brainsensing lead by measuring the amount of current required (compliancecurrent) to apply specific voltages to a microelectrode. The compliancecurrent is proportional to the amount of material that is oxidized orreduced at the microelectrode.

Voltage may be varied using any of the methods commonly used for in vivovoltammetry. These include cyclic voltammetry and pulse voltammetrymethods. An example of a fast scan cyclic voltammetry method uses avoltage sweep from −0.4 V to +1.2 V and back to −0.4 V is applied in astepwise manner over a period of 9 milliseconds. Ten sweeps per secondare made.

Pulse voltammetry methods are similar, but involve brief pulses atspecific voltages, intended to measure molecules with specific oxidationand reduction potentials.

Compliance currents are digitized by an analog-to-digital converter andmeasurements are transmitted to the host device from the electronicsmodule of the multimodal brain sensing lead. A number of measurementtrials may be averaged, either in the electronics module of themultimodal brain sensing lead or in a host device to which the data fromthe voltammetry sensor(s) on the lead is transmitted. A backgroundwaveform may be similarly generated and then subtracted from the signalof interest Timing is determined by an acquisition timing schedule,which is described later.

Rheoencephalography (REG) Measurement Acquisition

In an embodiment, rheoencephalography measurements are acquired using anembodiment of a multimodal brain sensing lead provided with fourmacroelectrodes for the purpose of estimating brain tissue impedancewhich varies with blood flow and neural activity. Rheoencephalographymeasurements are acquired by transmitting a low current waveform betweenone of two pairs of macroelectrodes, where the macroelectrodes are afirst, second, third and fourth macroelectrode. More specifically, inthis example, the low current waveform is transmitted between the pairof macroelectrodes comprising the first macroelectrode and the secondmacroelectrode. The voltage of the waveform is measured between the pairof macroelectrodes comprising the third macroelectrode and the fourthmacroelectrode. The third/fourth macroelectrode pair is positionedbetween the first/second macroelectrode pair, and along the same line asthe first/second macroelectrode pair.

The transmitted waveform may be a continuous sine wave or anintermittent pulsed square wave. The frequency of the waveform may beadjusted in order to preferentially measure the impedance of differentdensities of tissue (e.g., blood) or specific compartments (e.g.,extracellular space). The four macroelectrodes may be directly connectedto a host device to acquire rheoencephalographic measurements. In thiscase, the host device beneficially can be used to generate the waveformsand measure the voltages with circuitry in the host device. The timingof the rheoencephalographic measurements may be determined by anacquisition timing schedule, which is described more fully below.

Measurement Acquisition Timing

In an embodiment, acquiring measurements from at least two differentmeasurement modalities implemented in a multimodal brain sensing leadaccording to embodiments is accomplished according to a timing schedule.This schedule can vary considerably depending on which modalities arebeing acquired, and depending on Whether an electrical stimulationtherapy or therapies' is also being delivered to the patient at oraround the same time the measurements are being acquired (especiallywhere one or more macroelectrodes of the multimodal brain sensing leadare being used for the dual purposes of sensing physiological data fromthe patient and delivering stimulation to the patient).

Modality-Specific Timing Considerations

In an embodiment, the timing of raw data acquisition depends on manyfactors. Among these are two considerations: (1) from which modalitiesmeasurements are desired; and (2) what is the appropriate sampling ratefor each modality. Sampling rates that might be appropriate for eachmodality are discussed below.

Acquiring Neuronal Field Potential Measurements

In an embodiment, choosing an appropriate sampling rate for the neuronalfield potential measurement modality depends on the frequency range ofinterest. For example, and in general, there are two clinically relevantfrequency ranges for neuronal field potential signals. The first isbetween DC and approximately 125 Hz. This is the range of standard EEGrecording and covers delta, theta, beta, alpha, and gamma frequencyranges that are commonly used in clinical practice. A sampling rate of250 samples per second is sufficient to capture neuronal activity inthis range. The second range covers the high gamma frequencies,typically 125 to 500 Hz. A sampling rate of 1000 samples per second issufficient to capture neuronal activity in this range. For bothfrequency ranges, higher sampling rates are more desirable, butrecording (measuring) field potentials at the higher sampling ratesgenerally require more power and computational resources (e.g., from ahost device such as another implantable component of an implantablemedical device system that includes a multimodal brain sensing lead).

Acquiring Neuronal Single Unit Activity and Neuronal Multi Unit ActivityMeasurements

Action potentials of neurons typically have duration of 1-5milliseconds. When an objective of the measurement is to acquireinformation about neuronal action potentials that would be suitable forthe detection of spikes when they occur in a monitored signal and thesubsequent classification of the spikes (e.g., sorting spikes intogroups that have similar shapes and thus appear to have come from thesame neuron, allowing quantification of action potential rate for eachdistinguishable neuron in the signal), then acquiring five to tensamples per action potential would probably be sufficient, however moreare also acceptable. An appropriate sampling rate for recording actionpotentials in either the neuronal single unit activity measurementmodality or the neuronal multi unit activity modality may be 5-10thousand samples per second.

Acquiring Optical Measurements

Sensing modalities comprising information acquired using opticalcomponents include the optical blood volume measurement modality and theoptical oxygenation measurement modality. In some embodiments, twophysiological hemodynamic variables are measured using optical methods:heart rate; and blood oxygenation. Typical heart rates are below 180beats per minute or 3 beats per second. In some embodiments, in order toacquire a meaningful measurement, for example, one that will describe acardiac cycle, five to ten samples per heartbeat may be sufficient, butmore may be acceptable. An appropriate sampling rate for measuring heartrate may be 15-30 samples per second. Blood flow and oxygenation changesmay occur within 1-2 seconds, but more often changes may occur over tensof seconds to minutes. An appropriate sampling rate for blood flow andoxygen changes may be one to two samples per second.

Acquiring Voltammetry Measurements

Fast scan voltammetry measurements are made by scanning through a rangeof voltages. The scan duration depends on the voltage range and rate ofchange used, but a typical scan duration may be approximately 10milliseconds. In between scans, there usually is a variable lengthinter-scan interval, which can also be expressed as a scan-to-scaninterval, the reciprocal of which is the scan rate. For example, a 100millisecond scan-to-scan interval is 10 scans per second. Within eachscan, a sampling rate of 50-100 thousand samples per second may be used;if so, this would result in 500-1000 samples per 10 millisecond scan.The voltage scan waveform itself typically is generated at a much higherrate of 1 million samples per second using a voltage rate of 400 voltsper second. Alternatives to fast scan voltammetry measurements that mayalso be used with the multimodal brain sensing lead according toembodiments include pulse voltammetry measurement methods, such as: (1)sampled current polarography; (2) normal pulse voltammetry; (3)differential pulse voltammetry; and (4) square wave voltammetry.

Acquiring Rheoencephalography Measurements

Rheoencephalography may be performed using either a continuous sine waveor intermittent square pulses. For sine wave rheoencephalography, a lowamplitude forcing waveform in the range of 10-200 kHz is passed betweenone pair of electrodes and measured using a second pair of electrodes. Asampling rate of at least 10 times the forcing waveform frequencytypically must be used. For square pulse rheoencephalography, theforcing waveform is a square pulse with a short duration, for example 1millisecond, and a pulse-to-pulse interval is selected according to theexpected physiological rate of change, for example 1 Hz. A much lowersampling rate equal to the forcing waveform pulse frequency may be usedfor square pulse rheoencephalography.

Measurement Acquisition Timing Examples

Continuous Acquisition with Multiple Modalities

Referring to Table 1, an example will be described in which a multimodalbrain sensing lead is assumed to be configured to enable measurements inall of the sensing modalities discussed previously herein and in whichmeasurements from all of the sensing modalities are acquiredcontinuously with multiplexed timing. As for the field potentialmeasurement modality, in this example the acquisition of neuronal fieldpotentials is suspended during acquisition of rheoencephalographicmeasurements, and the acquisition of neuronal single unit activitymeasurements (or neuronal multi unit activity measurements, as the casemay be) is suspended during acquisition of voltammetry measurements.

TABLE 1 Modality Sampling Rate Notes Field Potential  250 samples/secondSuspended 1 sec during Measurement rheoencephalography Single Unit andMulti unit 5000 samples/second Suspended 1 sec during activityMeasurement voltammetry Optical Blood Volume  20 samples/second andOptical Blood Oxygenation Measurement

With reference to FIG. 21A, Table 2 illustrates the timing ofmeasurement acquisition for the various sensing modalities over oneminute. In Table 2, “FP” is “field, potential,” “SUA/MUA” is “singleunit activity/multi unit activity”; and “REG” is rheoencephalography.The dotted background in the first three rows of Table 2 is meant toindicate active measurement acquisition for the indicated sensingmodality (i.e., field potential measurement, single unit activitymeasurement (or multi unit activity measurement), and an opticalmeasurement modality). The white background in the bottom two rows ofTable 2 is meant to indicate no active acquisition for the indicatedmodality (i.e., voltammetry and rheoencephalography).

Continuous Acquisition with Electrical Stimulation Therapy Delivery

In some embodiments, a multimodal brain sensing lead not only may beconfigured to enable the acquisition of physiological information fromthe patient using two or more different sensing modalities but also maybe configurable to deliver a form of therapy to the patient. Forexample, when a multimodal brain sensing lead is used as part of animplantable responsive neurostimulation system, one or more of thesensing modalities may be used to acquire information from the patientthat is then processed by an implanted neurostimulator to determinewhether and, if so, when it might be appropriate to deliver a therapy tothe patient in response to the acquired information. One type of thetherapy the implant might determine is appropriate is a form ofelectrical stimulation (e.g., one or more bursts of pulsatilecurrent-controlled or voltage-controlled stimulation). One or morecomponents of the multimodal brain sensing lead may be used indelivering therapy to the patient. For example, one or more of themacroelectrodes on a multimodal brain sensing lead may be used todeliver the bursts of electrical stimulation when the implantedneurostimulator determines an epileptic seizure might be imminent basedon the acquired information.

In this situation, the implanted neurostimulator may be configured todeliver stimulation for 1 second. With reference to FIG. 21B, Table 3indicates that acquisition of measurements in the field potentialmeasurement modality and the single unit activity measurement (or multiunit activity measurement) modality are suspended while electricalstimulation is delivered so that sensing amplifiers associated withacquiring measurements in those sensing modalities are not overwhelmed(e.g., saturated). The dotted background in the top three rows of Table3 is meant to indicate active measurement acquisition for the indicatedsensing modality. The white background in Table 3 is meant to indicateno active acquisition for the indicated modality. The cross-hatchedbackground in the left-hand side of Table 3 for the field potential (FP)and single unit activity/multi unit activity (SUA/MUA) rows is meant toindicate that the acquisition of measurements in those modalities issuspended while electrical stimulation is being delivered (the time spanassociated with the cross-hatched area is meant to correspond to theone-second stimulation time).

Uses of Measurements Acquired from the Different Sensing Modalities

Multimodal measurements acquired using a multimodal brain sensing leadaccording to embodiments may be used in at least two general ways. Oneof these ways is to use the acquired data to visualize multiplephysiological variables over time. Another is to use the acquired datato trigger therapy delivery by a therapy delivery device or device(s),such as in a closed-loop therapy delivery system.

Data Visualization

An example of how information acquired from a multimodal brain sensinglead according to embodiments might be visualized by a user of animplantable medical device system that includes the lead was previouslydescribed with reference to FIG. 16, as well as Table 4. FIG. 16 is aseries of graphs tracking signals corresponding to measurements acquiredin each of five different sensing modalities over a common time window(in this case, five days). It will be appreciated that a user's beingable to visualize data acquired from different sensing modalities andfrom a localized region of the patient's brain over the same time periodmay be quite useful, for example, in initially diagnosing a patient orin evaluating the relative success of a particular treatment or therapy(e.g., drugs, electrical stimulation therapy, etc.). This sort of datavisualization may reveal complicated combinations of physiologicalpatterns that otherwise would be unobservable. The combinations ofpatterns may indicate physiological events or states occurring in thepatient which the patient's treating physician previously did not fullyappreciate. Thus, the physician's ability to easily comprehend thesecombinations of patterns of the data acquired from embodiments of amultimodal brain sensing lead may prompt the physician to try a type orform of clinical intervention than he or she otherwise would not havebeen prompted to try.

Table 4 represents one way of summarizing the data shown graphically inFIG. 16, A set of ‘events” labeled event “A”, event “9”, and event “C”are denoted in each of FIG. 16 and Table 4. In Table 4, an arrowpointing up is meant to indicate an increase in the measure of therelevant modality (e.g., an increase in the absolute value of a fieldpotential or the increase in the optical blood volume compared to a longterm or short term trend). An arrow pointing down is meant to indicate adecrease in the measure of the relevant modality.

TABLE 4 Sensing Modality A B C Field Potential Measurement ▴ ▴(summarizes graph 1602 of FIG. 16) Single Unit Activity Measurement ▴ ▴or Multi Unit Activity Measurement (summarizes graph 1604 of FIG. 16)Optical Measurement (e.g., ▴▾ Optical Blood Volume or Optical BloodOxygenation Measurement) (summarizes graph 1606 of FIG. 16) VoltammetryMeasurement ▴ ▴ (summarizes graph 1608 of FIG. 16) Rheoencephalography ▾▾ Measurement (summarizes graph 1610 of FIG. 16) = ▾ = decrease, ▴ =increase

Multimodal data visualization is very information rich, and therefore islikely to provide a much more comprehensive and superior representationof physiological changes over time than is data acquired using only asingle sensing modality (such as field potential measurement modality)or than is data acquired using multiple modalities but from differentprobes in contrast to the highly localized information that can beobtained when multiple different sensing modalities are implemented on asingle brain sensing lead.

FIG. 16 and Table 2 illustrate several examples. Each modality in FIG.16 exhibits a main broad peak and trough each day, along withsuperimposed irregularities that may be indicative of a physiologicalevent. Table 4 summarizes the irregularities and departures from theunderlying circadian rhythm for each modality. First, a circadian rhythmmay be observed when the data over five days from all five of therepresented modalities is appreciated, even though data from no singleone of the represented modalities might unambiguously reflect such acircadian rhythm. In other words, when data from all five modalitiesacquired over the same live days is viewed collectively, it seemsapparent that fluctuations in the measurements occur at different timesof day. Second, it may be observed that events “A”, event “B”, and event“C” are distinguishable from each other across modalities, but are notnecessarily distinguishable from each other within the confines of dataacquired using a single one of the different sensing modalities. Forexample, if one considers event “B” in Table 4 (corresponding to theinformation acquired from a field potential measurement sensingmodality) and compares it to event “C” in that same row of Table 4, theyappear the same because they both show an increase. However, when onelooks at the changes in the signals in Table 4 for all five sensingmodalities, then it can be appreciated that event “B” is characterizedby different features than is event “C”: for example, single unitactivity or multi unit activity increases during event “B” but does notchange during event C.

Similarly, if one compares event “A” to event “B” in Table 4 withrespect to the single unit activity measurement modality (or the multiunit activity measurement modality), both events show increases and nodramatic differences are apparent. However, when one looks at the natureof the signal in all five sensing modalities in Table 4, then it can beappreciated that event “A” is characterized by different features thanis event “B”: for example, the field potential measurement does notchange during event “A” but increases during event “B”, and therheoencephalography measurement decreases during event “A” but does notchange during event “B”.

Closed Loop Therapy Delivery System

As previously discussed herein, for example with reference to FIGS. 17,19, and 20, multimodal brain sensing leads according to embodiments maybe used beneficially with an implantable medical device system that hasa feature for delivering therapy based on feedback sensed from thepatient related to one or more conditions of the patients. A responsiveneurostimulation system is a particular example of such a closed-looptherapy delivery system, in which sensed information (such as from apatient with epilepsy) is processed by an implantable neurostimulatorand subjected to one or more detection algorithms running on theimplantable neurostimulator to detect patterns and/or sequencesoccurring in the sensed signals, and when a pattern and/or sequence isdetected, the neurostimulator “responds” by generating and thendelivering a form of electrical stimulation therapy (perhaps through thesame electrodes that are used to sense information from the patient inthe first instance).

In particular, FIG. 17 and its accompanying description (above)illustrate an example of how data acquired from two or more differentsensing modalities implemented on a multimodal brain sensing leadaccording to embodiments may be used in a closed-loop feedback therapydelivery system.

Clinical Examples

Embodiments of the multimodal brain sensing lead may be used, with othercomponents of an implantable medical device system such as a responsiveneurostimulation system or with components of other types of systemssuch as systems having all but the lead component external of thepatient, in a variety of clinical contexts. Some examples of clinicalcontexts include epilepsy, major depression, and Parkinson's disease.Some of these contexts are described briefly below.

Epilepsy Examples

Epilepsy patients experience seizures, which typically are accompaniedby abnormal electrographic activity, blood flow changes, tissueoxygenation changes, and neurotransmitter changes. Often, seizures beginin a specific area of the brain called the seizure focus. The locationof the seizure focus varies from patient to patient and an individualpatient may have multiple seizure foci. Physiological monitoring of theseizure focus can provide important diagnostic information, especiallythe timing of changes in physiological variables. For example, seizuresoften may be characterized by a transition from baseline to epileptiformEEG waveforms and are often preceded by decreases in blood flow at theseizure focus.

In an example, a patient visits a doctor because he has begun havingseizures. The doctor admits the patient to the hospital epilepsymonitoring unit (EMU) and has scalp electroencephalography (EEG)recordings performed. Based on the scalp EEG data, the doctor suspectsthe patient has seizures coming from the left anterior hippocampus ofthe temporal lobe. An intracranial EEG (iEEG) recording lead isimplanted (acutely) in the left anterior hippocampus to confirm thelocation of the seizure focus and count seizures. The data from thisdiagnostic procedure shows nearly constant abnormal epileptiformelectrographic activity in the anterior hippocampus, making it difficultif not nearly impossible to distinguish seizures from backgroundactivity.

Being able to count seizures and measure the seizure rate is importantin assessing a patient's condition and the effect of any treatments. Adoctor familiar with the literature describing changes in blood flow andoxygenation during seizures may decide to use an embodiment of amultimodal brain sensing lead such as described herein to monitor bothiEEG activity and hemodynamic changes, with the expectation that thiswill provide better information than iEEG activity alone.

To measure changes in physiological variables corresponding to the iEEGactivity and the hemodynamic changes, the doctor surgically implants amultimodal brain sensing lead configured with components enablingacquisition of measurements for at least two different sensingmodalities, namely, the neuronal field potential measurement modalityand an optical sensing modality (e.g., the optical blood volumemeasurement modality or the optical blood oxygenation measurementmodality). The multimodal brain sensing lead is stereotacticallyimplanted into the patient so that a distal portion thereof is situatedat or near the suspected seizure focus in the anterior hippocampus. Morespecifically, in this particular scenario, the distal portion of themultimodal brain sensing lead is implanted in the patient's anteriorhippocampus. A proximal portion of the lead is left external of thepatient so that it can be connected to an external host device.

After recovery from surgery, the patient is returned to the EpilepsyMonitoring Unit (EMU). In the EMU, the proximal portion of the lead isconnected to an external host device, in this case a small computer withcustom hardware and software necessary to connect to, communicate with,configure, and collect data acquired using the components for thesensing modalities provided in the implanted multimodal brain sensinglead. The system including the lead is then configured for collectingfield potential and hemodynamic measurements.

Neuronal field potential recording is used to record iEEG activityincluding electrographic spikes, waves and oscillatory activity fromneurons near the macroelectrodes on the multimodal lead. Some methods bywhich field potential measurements might be acquired using a multimodalbrain sensing lead according to embodiments has been described in somedetail previously herein. However, when the multimodal brain sensinglead is being used in a diagnostic procedure, for example, in an EMUwith an external host device receiving and processing signals sensedfrom the implanted lead, the methods may be adjusted to, for example,address the presence of electromagnetic noise generated by otherequipment in the patient's hospital environment.

In an example, two separate field potential channels are configured fordifferential recording. The field potential amplifiers (designated asthe field potential amplifier #1 and the field potential amplifier #2 inthis example) are located in the host device and not in the lead.Differential recording is selected to minimize electromagnetic noisefrom equipment in the room, and to help localize the seizure focus.Differential mode also is selected because a field potential signaldescribing differences between neural activities at two macroelectrodesis desired. This signal will reflect primarily activity near theelectrodes and subtract out background activity common to bothelectrodes.

There are four macroelectrodes (designated the first, second, third andfourth macroelectrodes in this example) available for field potentialrecording. A pair of macroelectrodes is selected to provide the inputsto each differential amplifier. The field potential amplifier #1 isconfigured for differential recording using the first and secondmacroelectrodes, the most distal electrodes, as inputs. This results ina differential field potential signal that describes population neuronalactivity near macroelectrodes #1 and #2 at the distal end of the lead.The field potential amplifier #2 is also configured for differentialrecording but using the more proximal third and fourth macroelectrodesas amplifier inputs. This results in a differential field potentialsignal that describes population neuronal activity near the third andfourth macroelectrodes in an area adjacent to and more proximal than thefirst and second macroelectrodes. If the seizure focus is closer to thefirst and second macroelectrodes, then the seizure signal will be largeron the output of field potential amplifier #1. If the seizure focus iscloser to the third and fourth macroelectrodes, then the seizure signalwill be larger on the output of the field potential amplifier #2.

Next, filter settings are selected. These field potential amplifierchannels will be used primarily for recording in the standard delta togamma EEG frequency range, approximately 3 to 100 Hz. A high-pass filteris set at 1 Hz, and a low-pass filter is set at 125 Hz. These settingsare typical for field potential recording. A 60 Hz notch filter isenabled because power line noise is expected to be present. Next, a gainsetting is selected. For this channel, a gain of 100 is selected becausefield potential voltage spikes of approximately ±10 mV are expected.This will result in approximately ±1 V output from the amplifier. Thisis within the amplifier's dynamic range, assuming the amplifier ispowered with 3.5 V. Finally, a sampling rate, the rate at which theanalog voltage measurements are converted to digital values, of 250samples per second is selected. This sampling rate is sufficient for EEGfield potential recording in the 3-100 Hz range.

After the host amplifiers and filters are configured, continuous iEEGfield potential data collection is started. While field potential dataare being collected, digitized voltage measurements are continuouslystored in the host device at a rate of 250 samples per second for eachamplifier channel Field potential data are stored in data files on thehost storage medium, which may be RAM memory or a hard drive.

Optical recording is used to measure blood flow, blood pressure, bloodoxygenation, heart rate, and breathing rate. The host device operatestogether with the optical sensing elements on the multimodal lead tomake optical measurements. The optical sensing elements on themultimodal lead consist of four 805 nm light emitting diodes (LEDs),four 630 nm LEDs, four photodiodes (PDs), one switched-capacitor (SC)amplifier, and one analog-to-digital converter (ADC). The external hostdevice controls measurement acquisition by sending control signalsthrough the two control wires of the lead.

The iEEG field potential and hemodynamic optical data stored in theexternal host device are used to identify and characterize seizures. TheiEEG field potential signal shows many long epileptiform discharges butthe doctor may be uncertain as to which ones are seizures. So, thedoctor may use acquired optical signals using one or more of the opticalsensing modalities of the multimodal brain sensing lead to help identifyreal seizures. The doctor may appreciate that the patient's breathing,heart rate, and blood pressure are likely to increase during seizures.The doctor may further appreciate that blood flow in the seizure focusincreases during a seizure and may decrease before the seizure. Thedoctor also may understand that blood oxygenation briefly decreases atthe onset of a seizure, then increases, then decreases again. Thus, inorder to identify clinical seizures, the doctor may look for thepresence of as many of these seizure patterns as possible in the signalsobtained from the multimodal brain sensing lead. If the doctor observesthat field potential channel #1 shows epileptiform discharges thatcorrelate with breathing rate, heart rate and blood pressure increasesfrom one or more of the optical assemblies on the lead that is beingused to acquire data in an optical measurement modality or modalities(e.g., to assess blood flow and oxygenation changes).

Based on these observations, the doctor may be able to identify andcount the patient's clinical seizures. The doctor further may be able touse this information to assess the effects of the epilepsy treatments towhich the patient is or may be subjected (e.g., electrical stimulationtherapy).

The data acquired from a multimodal brain sensing lead according toembodiments also may be used to determine which sensors and whichsignals from those sensors are likely to provide consistently) thehighest quality and most clinically relevant information. The highestquality signals may be defined as those which have the highestsignal-to-noise ratio and the fewest artifacts. The most clinicallyrelevant signals may be defined as those which are most highlycorrelated with physiological states and events of interest, such asseizures. For example, if a signal does not vary appreciably withseizures, it likely is not clinically relevant to the patient'sepilepsy. On the other hand, signals that change dramatically duringseizures are likely to be very clinically relevant.

These multimodal data may also be used for other purposes in epilepsypatients. If particular multimodal physiological patterns tend to occurprior to seizures, then the multimodal information may be used by thehost device to alert the patient or a caregiver that a seizure is likelyto occur, in this case, the patient or caregiver may be instructed orotherwise signaled to administer an antiepileptic treatment such as anoral drug that would reduce the likelihood or prevent the seizure fromoccurring. An additional use for the multimodal information may be todetect Sudden Unexplained Death in Epilepsy (SUDEP) Imminent SUDEP wouldbe indicated by cessation of cardiac activity and respiration andpossibly dramatic changes in electrographic activity. The host devicemay be configured to alert patient caregivers in this situation so thatthey may attempt to treat or revive the patient.

Major Depression

Abnormal blood flow in the frontal lobes is believed to be associatedwith major depression. Abnormal blood flow can be measured using opticalsensing or rheoencephalography. It is likely that electrographic changesare also associated with depression symptoms. These changes can bemeasured using either macroelectrodes or microelectrodes. There are alsoneurotransmitter changes associated with depression, especially in theserotonergic system. An example of a clinical application of amultimodal brain sensing lead according to embodiments in majordepression would include implanting a multimodal depth brain sensinglead so that a distal portion thereof is in the vicinity of Area 25 orthe anterior limb of the interior capsule/nucleus accumbens (ALIC/NA).The multimodal brain sensing lead may be configured so that each of thefield potential measurement modality, the single unit activity or multiunit activity measurement modality, the optical measurement modality(blood volume and/or blood oxygenation), and the rheoencephalographymodalities are available. Once the lead is implanted, multiple differentones of the available sensing modalities can be used to acquireinformation from which estimates of blood flow, optical blood volume andvariables related to rheoencephalography can be made (e.g., in a hostdevice or manually by the physician). The field potential measurementmodality and the single unit activity measurement (or multi unitmeasurement) modality may be availed upon to measure electrographicchanges and to record action potential behavior at the level of a singleneuron or at the level of a small group of neurons.

The multimodal depth lead can be used in the following manner fortreating major depression. First, the lead is implanted in an area ofthe brain expected to exhibit symptoms correlated with affective changesin major depression. Examples of target areas include but are notlimited to Area 25 and the ALIC/NA. The multimodal lead would beconnected to a host device. The host device would serve to power andcontrol the multimodal lead, and to process and store signals receivedfrom the lead, and to communicate with other external devices includingbut not limited to wireless telemetry transceivers connected to externalcomputing platforms. Examples of the host device include but are notlimited to a small host device implanted in a surgically created defectof the patient's skull, or an external host device such as a computer.Together, the host device and the multimodal lead collect multimodalmeasurements using an interleaved timing scheme that repeats atscheduled intervals. The scheduled interval is configured to provide atime-series record of physiological measurements that has sufficienttemporal resolution to detect clinically meaningful physiologicalchanges related to the patient's disease state. The sampling intervalmay be different for each modality, and may vary depending on thepatient's physiological state as detected by the host-lead system. Forexample, the sampling interval for all of the modalities may be onesample per second, one sample per minute, one sample per hour, or varybetween sensing modalities. For example, optical blood flow measurementscould be one per minute while the macroelectrode neuronal fieldpotential measurements could be 200 samples per second.

Importantly, voltammetry measurements may be used to measure eitherneurotransmitter levels, such as serotonin, dopamine, norepinephrine, orlevels of therapeutic drugs such as serotonergic or dopaminergicpharmaceuticals. Thus, data acquired using a voltammetry sensingmodality can be used to provide a view of neurotransmitter and drugfluctuations over time, which can aid a physician in prescribing andadjusting treatment drugs

In sum, data from a multimodal brain sensing lead may also be usedbeneficially, in conjunction with another component or componentsconfigured to process and analyze the data (e.g., an external hostdevice or an implanted host device as part of an implantable medicaldevice system), in an application to diagnose and treat a patientexperiencing a depressive disorder. The lead may be used in this mannerto accurately diagnose the patient's clinical state and prescribetreatment. Diagnosis will be aided because a time series record ofsymptoms associated with depression will be available, as obtained fromthe local information acquired by the one or more sensing modalitiesimplemented on the lead. In addition to subjective information elicitedfrom the patient about his or her symptoms of depression, the physiciancan beneficially use objective evidence obtained from the differentsensing modalities to determine such things as whether the patient is ina depressed state, if so, for how long the state has persisted; acontinuous history of the patient's history of depressed states; theduration and severity of each state; and the intervals between depressedstates. The physician will use this information to assess the patient'sresponses to treatment and to guide future treatment prescriptions.

In addition, when used in conjunction with a closed loop therapydelivery system, a multimodal brain sensing lead according toembodiments can be used to identify changes in physiological measuresthat may predict whether the patient will develop depression symptoms.Based on specific changes in the physiological measures, therapeuticinterventions may be initiated so that depression symptoms do notdevelop. Such a prophylactic approach may also be used to administertherapies in order to maintain a desired physiological state so thattherapy is provided only as often and to the extent that it is Deeded.

Parkinson's Disease

Embodiments of a multimodal brain sensing lead also may be usedbeneficially, in conjunction with another component or componentsconfigured to process and analyze the data (e.g., an external hostdevice or an implanted host device as part of an implantable medicaldevice system), to assess Parkinson's disease symptoms. Parkinson'sdisease is characterized by a loss of dopaminergic neurons in thesubstantia nigra (SN). This leads to abnormally high activity in thesubthalamic nucleus (STN), which the substantia nigra normally inhibitsthrough synaptic connections. Other brain areas that receive input fromthe substantia nigra and subthalamic nucleus also may show abnormalneural activity. Nearly all Parkinson's disease patients also takemedications such as Sinemet (carbidopa-levodopa), the concentrations ofwhich at or near the relevant structures in the patient's brain may beof interest to the treating physician.

A multimodal brain sensing lead according to embodiments may be usedbeneficially in a therapy for treating Parkinson's disease patients byimplanting a distal portion of the lead in the subthalamic nucleus oranother brain area and using it to monitor physiological variables anddrug levels. In an example, a distal portion of a multimodal depth brainsensing lead is implanted in a subthalamic nucleus (STN). The lead isconfigured with several sensing modalities: the field potential sensingmodality (i.e., to measure field potentials using macroelectrodes); theneuronal single unit activity measurement modality (and/or multi unitactivity measurement modality) (i.e., to measure action potentials usingmicroelectrodes); the voltammetry measurement modality (i.e., to measureneurotransmitter (e.g., dopamine) levels using the voltammetrycomponents on the lead); the optical measurement modality (e.g., theoptical blood volume measurement modality) (i.e., to estimate blood flowusing the optical assembly(ies) on the lead. The single unit activitymeasurement modality and the multi unit measurement modality each may beexpected to acquire data that show increased oscillatory activity in thebeta frequency range when Parkinson's disease symptoms are present. Thevoltammetry sensor implemented by the relevant components on the leadmay be expected to measure changes in Sinemet drug levels as bloodlevels of the drug increase after oral administration and then decreaseas the drug is metabolized.

In this particular example, the multimodal brain sensing lead may beconnected to an implanted host device that controls data acquisition andprocesses and stores measurement data. Electrophysiological measurementsmay be acquired at 200 samples per second. Optical measurements may beacquired at a rate of once per minute. Voltammetry measurements also maybe acquired at a rate of once per minute. A treatment algorithm runningin the host device may be configured to analyze the time-series ofphysiological measurements and then to use the time-series patterns todetermine whether and, if so, when to deliver a therapy to the patientand according to what therapy parameters (or therapy settings), based ona pre-determined set of therapy settings defined by the physician. Forexample, when Sinemet blood levels are above a threshold pre-determinedby the physician, a system including the multimodal brain sensing leadand the implanted host device may be configured to deliver pulsatileelectrical stimulation through the macroelectrodes at a low level (e.g.,130 Hz, 160 microseconds per phase, biphasic square pulses with a 100microsecond inter-phase interval, at 1 volt amplitude). The system maybe programmed such that, if Sinemet blood levels exceed the threshold,the stimulation amplitude may be increased to 3 volts. Alternatively,the system could include a feature whereby different amplitude settings(including zero volts) are mapped to different Sinemet blood levelranges so that as the Sinemet blood level gradually decreases, thestimulation amplitude may be gradually increased, thus maintaining thecombined therapeutic effect of Sinemet and stimulation. Additionally,when beta oscillations are observed (for example, by the implanted hostdevice) as a result of measurements acquired from the multimodal brainsensing lead in either the multi unit activity measurement modality orthe single unit activity measurement modality, and the beta oscillationsare characterized by an amplitude and duration in excess of levelspre-determined by the physician, the implanted host device may beconfigured to increase the amplitude of the electrical stimulation to 3volts until the data obtained from the lead sensors indicates that thebeta oscillation subsides.

Closed Loop Therapy Delivery

As previously discussed herein, one or more multimodal brain sensingleads may be used as component(s) of a closed loop therapy deliverysystem. Such a system may trigger delivery of a therapy to the patient(or generation and delivery of a therapy to the patient) in response tothe processing and analyze of data acquired from one or more of thesensing modalities implemented on the multimodal brain sensing lead(s).Alternatively or additionally, such a system may adjust a form oftherapy automatically based on the information that is being acquiredusing one or more of the sensing modalities implemented on themultimodal brain sensing lead(s), for example, in real time.

Generally, the components of a closed loop therapy system may beconfigured to collect, process, store and analyze data acquired from oneor more of the measurement modalities available on the multimodal brainsensing lead(s). For example, an algorithm running on a host devicewould use these data to determine when to deliver therapy and how muchto deliver. Therapy may take the form of automatic drug delivery intothe body from a drug pump, or neuromodulatory electrical stimulationthrough the macroelectrodes into the tissue surrounding the distalportion of the lead. For example, when a closed loop system detectsdecreased levels of blood flow and/or neurotransmitter levels (e.g.,serotonin or dopamine), the system may be configured to automaticallydeliver a therapeutic dose of a serotonergic drug such as fluoxetine.Therapy may also take the form of electrical stimulation deliveredthrough the macroelectrodes on the lead. The stimulation settings (i.e.,electrode selection, waveform, polarity, pulse width, pulse frequency,pulse amplitude, current-controlled or voltage-controlled) may bepredetermined by the physician. Different stimulation parameters couldbe selected by the physician to be delivered based on the physiologicalmeasurements processed and analyzed by the host device and/or based onthe physician's assessment of those measurements when the results aredisplayed to the physician, for example, as a snapshot in time of thebehavior of the neural tissue in the highly localized region of thebrain in which the distal portion of the lead(s) is/are situated.

Examples of Host Devices

A host which accepts and processes and otherwise reacts to data obtainedfrom multimodal brain sensing lead(s) according to embodiments mayinclude an implantable responsive neurostimulator such as describedbelow.

FIG. 19 illustrates one example of an implantable medical device systemhaving both implantable and external components and with whichmultimodal brain sensing leads according to embodiments may bebeneficially used. A host device 2006 is shown implanted in a patient2024 (in this case, in the cranium of the patient). The host device 2006may have various elements that allow it to process and analyze dataacquired using the various sensing modalities of the multimodal brainsensing lead (e.g., a control module 2008, a power supply 2010 and aclock 2012). The host device further may have one or more elements thatcontrol the timing of the acquisition of data from one sensing modalityas compared with another sensing modality. In addition, the host devicemay have elements that allow it to react to the data acquired from thevarious sensing modalities implemented on the multimodal brain sensinglead, such as by generating and delivering a burst or bursts ofpulsatile electrical stimulation to the patient. In some implantablemedical device systems, the multimodal brain sensing lead may includecomponents such as macroelectrodes that can be used for sensing in oneor more of the sensing modalities and also for delivering electricalstimulation to the patient as one reaction to data sensed from the lead.

Generally, the implantable host device 2006 of the implantable medicaldevice system shown in FIG. 19 is able to detect neurological events(e.g., spatial or temporal patterns or sequences believed to correspondin some way to a patient's condition or disorder), record and/or log theneurological events in memory, and then communicate the data it acquiresand the events it detects to one or more external components from whichthe data and event information can be used by a physician in furtherdiagnosing or otherwise treating the patient. An implantable medicaldevice system comprising a responsive neurostimulation system, forexample, may be configurable to detect events that are understood to berelated to some aspect of a patient's epilepsy, e.g., seizures, seizureonsets or precursors to seizures.

In a responsive neurostimulation system, the implanted neurostimulator,e.g., the host device 2006 in FIG. 19 may be configured to recordneurological signals, such as electrocorticographic (ECoG) waveforms, todetect and analyze ECoG signals, and/or to create a log of suchdetection and analysis. (EEG signals represent aggregate neuronalactivity potentials detectable via sensors applied to a patient's scalp.ECoG signals, which are deep-brain or cortical surface counterparts tothe EEG signals, are detectable via sensors implanted on or under thedura mater, and usually within the patient's brain. Unless otherwisenoted herein, the term “EEG” is used generically herein to refer to bothEEG and ECoG signals, the ECoG signals generally being considered asubset of EEG signals.)

A responsive neurostimulator typically is programmable and typically hasa relatively large number and variety of parameters that can be set andsubsequently be modified in a programming session after theneurostimulator is implanted in a patient. When used to process andanalyze signals obtained from the various measurement modalitiesimplemented in a multimodal brain sensing lead according to embodiments,programming the neurostimulator may involve specifying parameter valuesthat: will control signals that are generated and delivered to thedistal portion of the lead necessary to acquire a given measurement fora given sensing modality; process signals that are received hack fromthe components used in the lead to implement the various modalities(e.g., amplifier gain settings or filter settings); and determine whichpatterns or sequences or combinations of the same will be determined toconstituted “events” by the neurostimulator when they occur in the dataacquired from the various sensing modalities implemented on the lead.Thus, for example, the responsive neurostimulator may be programmed tobegin recording detected ECoG signals satisfying certain detectionparameters or criteria (e.g., based on a combination of parametervalues) from the patient 2024 at the onset or otherwise as a result ofictal activity. The responsive neurostimulator may be configured torecord signals or values corresponding or related to signals at timesbefore, during and after the detection criteria have been met. Theresponsive neurostimulator may be configured to continue recording untilthe ictal activity stops.

Optionally, the responsive neurostimulator 2006 saves relevantrecordings, or sampling thereof, to a local memory in order to preserveit for later downloading to an external device, such as one of theprogrammers 2020A, 2020B, 2020C and 2020D or the patient remote monitor2026 shown in FIG. 19. The responsive neurostimulator may also create alog of the events (e.g., ictal activity) that it records. In oneexample, the responsive neurostimulator records and/or logs the date andtime when an event begins and ends, the duration of the event,indications of the intensity of the event, etc.

The responsive neurostimulator may also be configured to record and/orpreserve data corresponding to ECoG signals upon the initiation of someaction (e.g., swiping an external magnet near the site at which theresponsive neurostimulator is implanted) by the patient, a caregiver orphysician.

It should be appreciated that an implantable host device useful with amultimodal brain sensing lead according to embodiments may be configuredto detect any kind of neurological condition or disorder that has arepresentative signature relative to data acquired from one of theavailable sensing modalities or relative to data acquired from somecombination of the available sensing modalities, for example, in acertain window of time. While an implantable host device in the form ofa responsive neurostimulator is described above, sometimes withreference to an epilepsy application, it should be appreciated thatembodiments of the multimodal brain sensing lead may be useful with agreat variety of host devices (implantable or external to the patient)for a great many applications. By way of example and not by way oflimitation, the host device may be only configured as a diagnostic tool,and therefore may not have any capacity to react to data acquired from asensing modality implemented on the lead with a therapy. The host devicemay be used with embodiments of the multimodal brain sensing lead inapplications relevant to almost any conceivable neurological conditionor disorder, including but not limited to studies and therapies relatingto epilepsy, movement disorders, psychiatric disorders, headaches,obesity, gastroenterological disorders, stroke recovery, Alzheimer'sdisease, and so on and so forth. The richness of the information aboutlocalized regions of a patient's brain that can be obtained usingembodiments of the multimodal brain sensing lead is expected to betterinform diagnosis and treatment for many diverse and complex disordersand conditions.

Various example embodiments are thus described. All statements hereinreciting principles, aspects, and embodiments as well as specificexamples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope, therefore, is notintended to be limited to the embodiments shown and described herein.

What is claimed is:
 1. A system for measuring physiological informationfrom a patient, the system comprising: a lead configured to be implantedin the patient, the lead comprising: a body having a distal portion, aplurality of lead components at the distal portion, wherein theplurality of lead components includes a plurality of macroelectrodes, aplurality of microelectrodes, and at least one optical assembly, and alead electronics module comprising a lead signal processor configured toprocess signals from one or more of the plurality of lead components toobtain at least one of a plurality of first measurements including aneuronal single unit activity measurement, a neuronal multi unitactivity measurement, an optical blood volume measurement, or an opticalblood oxygenation measurement; and a host coupled to the lead, the hostcomprising: a host control module configured to generate and output hostcontrol signals, a host power supply configured to provide power, and ahost signal processor configured to process signals from one or more ofthe plurality of lead components to obtain at least one of a pluralityof second measurements including neuronal field potential measurement ora rheoencephalography measurement, wherein the host control module andthe host power supply are electrically coupled to the lead electronicsmodule, and the lead electronics module is configured to selectivelyenable, based on the host control signals: a) a first sensing modalitythat provides one of the plurality of first measurements to the host byelectrically coupling at least one of the plurality of lead componentsto at least one of: i) an input to the lead signal processor, and ii)the host power supply, and electrically coupling an output of the leadsignal processor to the host, and b) a second sensing modality thatenables the host signal processor to obtain one of the plurality ofsecond measurement by electrically coupling at least one of theplurality of lead components to the host signal processor, bypassing thelead signal processor.
 2. The system of claim 1, wherein: the leadelectronics module is configured to electrically couple a firstmicroelectrode to a first input of the lead signal processor andelectrically couple a second microelectrode to a second input of thelead signal processor, to selectively enable the first sensing modalitythat provides a first measurement corresponding to the single unitactivity measurement and the multi unit activity measurement, andelectrically couple an output of lead signal processor to the host. 3.The system of claim 2, wherein the lead signal processor comprises anamplifier and the first input corresponds to a first input of theamplifier, and the second input corresponds to a second input of theamplifier.
 4. The system of claim 1, wherein: the lead electronicsmodule is configured to electrically couple a microelectrode to a firstinput of the lead signal processor and electrically couple amacroelectrode to a second input of the lead signal processor, toselectively enable the first sensing modality that provides a firstmeasurement corresponding to the single unit activity measurement andthe multi unit activity measurement, and electrically couple an outputof the lead signal processor to the host.
 5. The system of claim 4,wherein the lead signal processor comprises an amplifier and the firstinput corresponds to a first input of the amplifier, and the secondinput corresponds to a second input of the amplifier.
 6. The system ofclaim 1, wherein: the at least one optical assembly comprises at leastone light emitting diode (LED) and at least one photodetector, and thelead electronics module is configured to electrically couple a LED tothe host power supply to illuminate the LED and electrically couple aphotodetector to an input of the lead signal processor, to selectivelyenable the first sensing modality that provides a first measurementcorresponding to either of the optical blood volume measurement, or theoptical blood oxygenation measurement, and electrically couple an outputof the lead signal processor to the host.
 7. The system of claim 6,wherein: the lead signal processor comprises an amplifier and ananalog-to-digital convertor, wherein an output of the amplifier iscoupled to an input of an analog-to-digital convertor, and the input ofthe lead signal processor corresponds to an input of the amplifier, andthe output of the lead signal processor corresponds to an output of theanalog-to-digital convertor.
 8. The system of claim 1, wherein: the leadelectronics module is configured to electrically couple a firstmacroelectrode to the host signal processor, to selectively, enable thesecond sensing modality that enables the host signal processor to obtaina second measurement corresponding to the field potential measurementand to electrically couple a second macroelectrode to the host signalprocessor.
 9. The system of claim 1, wherein: the lead electronicsmodule is configured to electrically couple each of a firstmacroelectrode, a second macroelectrode, a third macroelectrode, and afourth macroelectrode to the host signal processor to selectively,enable the second sensing modality that enables the host signalprocessor to obtain a second measurement corresponding to therheoncephalography measurement.
 10. The system of claim 1, wherein thehost control module is configured to change control signals during aperiod of time, and the lead electronics module is configured to, basedon a change in control signals: electrically couple a first set of theplurality of lead components to the lead signal processor to obtain atleast one of the plurality of first measurements for a first portion ofthe period of time, and electrically couple a second set of theplurality of lead components to the host signal processor to obtain oneof the plurality of second measurements for a second portion of theperiod of time.
 11. The system of claim 10, wherein the host controlmodule is further configured to change control signals during the periodof time, and the lead electronics module is configured to, based on achange in control signals, to electrically couple a third set of theplurality of lead components to the lead signal processor to obtainanother one of the plurality of first measurements for a third portionof the period of time.
 12. The system of claim 1, wherein the hostcontrol module is configured to change control signals during a periodof time, and the lead electronics module is configured to, based on achange in control signals: electrically couple a first set of theplurality of lead components to the lead signal processor to obtain afirst of the plurality of first measurements for a first portion of theperiod of time, and electrically couple a second set of the plurality oflead components to the lead signal processor to obtain a second of theplurality of first measurements for a second portion of the period oftime, while electrically decoupling the first set of the plurality oflead components from the lead signal processor to suspend the obtainingof the first of the plurality of first measurements.
 13. The system ofclaim 12, wherein the first of the plurality of first measurements is anactivity measurement and the second of the plurality of firstmeasurements is a voltammetry measurement.
 14. The system of claim 1,wherein the host control module is configured to change control signalsduring a period of time, and the lead electronics module is configuredto, based on a change in control signals: electrically couple a firstset of the plurality of lead components to the host signal processor toobtain a first of the plurality of second measurements for a firstportion of the period of time, and electrically couple a second set ofthe plurality of lead components to the host signal processor to obtaina second of the plurality of second measurements for a second portion ofthe period of time, while electrically decoupling the first set of theplurality of lead components from the host signal processor to suspendthe obtaining of the first of the plurality of second measurements. 15.The system of claim 14, wherein the first of the plurality of secondmeasurements is a field potential measurement and the second of theplurality of second measurements is a rheoencephalography measurement.16. The system of claim 1, wherein: the host further comprises a therapymodule configured to output an electrical stimulation signal, the leadelectronics module is electrically coupled to the therapy module, thehost control module is configured to output control signals during aperiod of time, and the lead electronics module is configured to, basedon the control signals, electrically couple one or more of the pluralityof lead components to the therapy module to deliver the electricalstimulation signal to the patient.
 17. The system of claim 16, whereinthe host control module is configured to output control signals duringthe period of time, and the lead electronics module is configured to,based the control signals, electrically couple a first set of theplurality of lead components to the lead signal processor to obtain afirst of the plurality of first measurements during the period of time.18. The system of claim 17, wherein the first of the plurality of firstmeasurements is an optical measurement.
 19. The system of claim 16,wherein the host control module is configured to output control signalsduring the period of time, and the lead electronics module is configuredto, based on the control signals, suspend the obtaining of a second ofthe plurality of first measurements.
 20. The system of claim 19, whereinthe second of the plurality of first measurements is an activitymeasurement.
 21. The system of claim 16, wherein the host control moduleis configured to output control signals during the period of time, andthe lead electronics module is configured to, in response to the controlsignals, suspend the obtaining of a first of the plurality of secondmeasurements.
 22. The system of claim 21, wherein the first of theplurality of second measurements is a field potential measurement.